Cancer by Sfakianakis Alexandros: 07/27/16

Τετάρτη 27 Ιουλίου 2016

Biodistribution of anti-5T4-ADC by FMT Imaging

Understanding a drug's whole-body biodistribution and tumor targeting can provide important information regarding efficacy, safety and dosing parameters. Current methods to evaluate biodistribution include in vivo imaging technologies like positron electron tomography and single-photon emission computed tomography or ex vivo quantitation of drug concentrations in tissues using autoradiography and standard biochemical assays. These methods use radioactive compounds or are cumbersome and do not give whole-body information. Here, for the first time we show the utility of fluorescence molecular tomography (FMT) imaging to determine the biodistribution and targeting of an antibody-drug conjugate (ADC). An anti-5T4-Antibody (5T4-Ab) and 5T4-ADC were conjugated with a near-infrared (NIR) fluorophore VivoTag 680XL (VT680). Both conjugated compounds were stable as determined by SEC-HPLC and plasma stability studies. Flow cytometry and fluorescence microscopy studies showed that VT680 conjugated 5T4-ADC specifically bound 5T4 expressing cells in vitro, and also exhibited a similar cytotoxicity profile as the unconjugated 5T4-ADC. In vivo biodistribution and tumor targeting in an H1975 subcutaneous xenograft model demonstrated no significant differences between accumulation of VT680 conjugated 5T4-Ab or 5T4-ADC in either normal tissues or tumor. Additionally, quantitation of heart signal from FMT imaging showed good correlation with the plasma pharmacokinetic profile suggesting that it (heart FMT imaging) may be a surrogate for plasma drug clearance. These results demonstrate that conjugation of VT680 to 5T4-Ab or 5T4-ADC does not change the behavior of native biologic and FMT imaging can be an useful tool to understand biodistribution and tumor targeting kinetics of antibodies, ADCs and other biologics.

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Presurgical MMP inhibition blocks breast cancer metastasis

Breast cancer has the second highest death toll in women worldwide, despite significant progress in early diagnosis and treatments. The main cause of death is metastatic disease. Matrix metalloproteinases (MMPs) are required for the initial steps of metastasis, and have therefore been considered as ideal pharmacological targets for anti-metastatic therapy. However, clinical trials of MMP inhibitors were unsuccessful. These trials were conducted in patients with advanced disease, beyond the stage when these compounds could have been effective. We hypothesized that early treatment with a selective MMP inhibitor between the time of diagnosis and definitive surgery, the so-called "window-of-opportunity," can inhibit metastasis and thereby improve survival. To investigate our hypothesis we used the 4T1 mouse model of aggressive mammary carcinoma. We treated the animals with SD-7300, an oral inhibitor of MMP-2, -9 and -13, starting after the initial detection of the primary tumor. Seven days later the primary tumors were excised and analyzed for MMP activity, and the SD-7300 treatment was discontinued. After four weeks the animals were sacrificed and their lungs analyzed histologically for number of metastases and metastatic burden (metastases' area / lung section area). SD-7300 treatment inhibited 70-80% of tumor-associated MMP activity (P = 0.0003), reduced metastasis number and metastatic burden by 50-60% (P = 0.002; P = 0.0082, respectively), and increased survival (92% vs. 66.7%; P = 0.0409), relative to control vehicle. These results show that treatment of early invasive breast cancer with selective MMP inhibitors can lower the risk of recurrence and increase long-term disease-free survival.

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Targeting mitochondria in drug-resistant osteosarcoma

Doxorubicin is one of the leading drugs for osteosarcoma standard chemotherapy. 40-45% of high grade osteosarcoma patients are unresponsive, or only partially responsive, to doxorubicin, due to the overexpression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). The aim of this work is to improve doxorubicin-based regimens in resistant osteosarcomas. We used a chemically modified mitochondria-targeted doxorubicin (mtDox) against Pgp-overexpressing osteosarcomas with increased resistance to doxorubicin. Unlike doxorubicin, mtDox accumulated at significant levels intracellularly, exerted cytotoxic activity, induced necrotic and immunogenic cell death in doxorubicin-resistant/Pgp-overexpressing cells, fully reproducing the activities exerted by anthracyclines in drug-sensitive tumors. mtDox reduced tumor growth and cell proliferation, increased apoptosis, primed tumor cells for the recognition by the host immune system and was less cardiotoxic than doxorubicin in pre-clinical models of drug-resistant osteosarcoma. The increase in doxorubicin resistance was paralleled by a progressive upregulation of mitochondrial metabolism. By widely modulating the expression of mitochondria-related genes, mtDox decreased mitochondrial biogenesis, the import of proteins and metabolites within mitochondria, mitochondrial metabolism and the synthesis of ATP. These events were paralleled by increased reactive oxygen species production, mitochondrial depolarization and mitochondria-dependent apoptosis in resistant osteosarcoma cells, where doxorubicin was completely ineffective. We propose mtDox as a new effective agent with a safer toxicity profile compared to doxorubicin that may be effective for the treatment of doxorubicin-resistant/Pgp-positive osteosarcoma patients, who strongly need alternative and innovative treatment strategies.

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Tariquidar and paclitaxel therapy in ovarian cancer

The overexpression of permeability-glycoprotein (P-gp), an ABC transporter involved in the cellular exclusion of chemotherapeutic drugs, is a major factor in paclitaxel-resistant ovarian cancer (OvCa). However, in clinical trials, co-administration of P-gp inhibitors and anti-cancer drugs has not resulted in the efficient reversal of drug resistance. To improve administration, we encapsulated the 3rd generation P-gp inhibitor, tariquidar (XR-9576, XR), alone or in combination with paclitaxel (PCT) in liposomes (LP). After optimization, the liposomes demonstrated favorable physicochemical properties and the ability to reverse chemoresistance in experiments using chemosensitive/chemoresistant OvCa cell line pairs. Analyzing publicly available datasets, we found that overexpression of P-gp in OvCa is associated with a shorter progression-free and overall survival. In vitro, LP(XR) significantly increased the cellular retention of rhodamine 123, a P-gp substrate. LP(XR,PCT) synergistically inhibited cell viability, blocked proliferation, and caused G2/M arrest in paclitaxel-resistant SKOV3-TR and HeyA8-MDR cell lines overexpressing P-gp. Holographic imaging cytometry revealed that LP(XR,PCT) treatment of SKOV3-TR cells induced almost complete mitotic arrest, while laser scanning cytometry showed that the treatment induced apoptosis. In proof of concept preclinical studies, LP(XR,PCT), when compared with LP(PCT), significantly reduced tumor weight (43.2% versus 16.9%, p=0.0007) and number of metastases (44.4% versus 2.8%, p=0.012) in mice bearing orthotopic HeyA8-MDR ovarian tumors. In the xenografts, LP(XR,PCT) efficiently induced apoptosis and impaired proliferation. Our findings suggest that co-delivery of a P-gp inhibitor and paclitaxel using a liposomal platform can sensitize paclitaxel-resistant OvCa cells to paclitaxel. LP(XR,PCT) should be considered for clinical testing in patients with P-gp-overexpressing tumors.

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TP53 and VEGF/VEGFR Inhibitor Response

TP53 tumor suppressor gene mutations are amongst the most frequent abnormalities in cancer, affecting approximately 40% of patients. Yet, there is no accepted way to target these alterations in the clinic. At the same time, antagonists of vascular endothelial growth factor (VEGF) receptor (VEGFR) or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. While only a subset of patients benefit from these anti-angiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations up-regulate VEGF-A and VEGFR2. We prospectively enrolled 500 patients, to be interrogated by comprehensive genomic profiling (CGP) (next generation sequencing, 236 genes), and to be matched, whenever possible, with targeted agents. Herein, we analyze outcomes based on VEGF/VEGFR inhibitor treatment and presence of TP53 mutations. Of the 500 patients, 188 (37.6%) (with {greater than or equal to}1 alteration) were treated; 106 (56% of 188) had tumors that harbored TP53 mutations. VEGF/VEGFR inhibitor therapy was independently associated with improvement in all outcome parameters (rate of stable disease (SD) {greater than or equal to}6 months/partial and complete remission (PR/CR) (31% versus 7%; TP53-mutant patients (who received no other molecular-matched agents) treated with versus without VEGF/VEGFR inhibitors), time-to-treatment failure and overall survival (multivariate analysis: all p{less than or equal to} 0.01)) for the patients harboring TP53-mutant cancers, but improvement was not seen in any of these parameters for patients with TP53 wild-type neoplasms. We conclude that TP53 mutations predict sensitivity to VEGF/VEGFR inhibitors in the clinic. TP53 alterations may therefore be a ready biomarker for treatment with anti-angiogenesis agents, a finding of seminal importance across the cancer field.

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Decoding intratumoral heterogeneity

Differential diagnosis and therapy of heterogeneous breast tumors poses a major clinical challenge. To address the need for a comprehensive, non-invasive strategy to define the molecular and functional profiles of tumors in vivo, we investigated a novel combination of metabolic positron emission tomography (PET) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in the polyoma virus middle T transgenic mouse model of breast cancer. The implementation of a voxelwise analysis for the clustering of intra- and intertumoral heterogeneity in this model resulted in a multiparametric profile based on [18F]FDG-PET and DW-MRI which identified 3 distinct tumor phenotypes in vivo, including solid acinar and solid nodular malignancies as well as cystic hyperplasia. To evaluate the feasibility of this approach for clinical use, we examined estrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) breast tumors from 5 patient cases using DW-MRI and [18F]FDG-PET in a simultaneous PET/MRI system. The post-surgical in vivo PET/MRI data was correlated to whole-slide histology using the latter traditional diagnostic standard to define phenotype. By this approach, we showed how molecular, structural (microscopic, anatomic) and functional information could be simultaneously obtained non-invasively to identify precancerous and malignant subtypes within heterogeneous tumors. Combined with an automatized analysis, our results suggest that multiparametric molecular and functional imaging may be capable of providing comprehensive tumor profiling for non-invasive cancer diagnostics.

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Metabolic regulation of CTL by p53

Repetitive stimulation of T cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and anti-tumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS dependent JNK activation that leads to its activation induced cell death (AICD). Since tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope reactive T cells developed on p53 knock-out (KO) background, we determined its role in regulating anti-tumor T cell function. Our data shows that as compared to h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFN-γ secretion, cytolytic capacity, expression of stemness gene signature and decreased TGF-β signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells . Pharmacological inhibition of human TCR transduced T cells using a combination of p53 inhibitors also potentiated the T cell effector function and improved persistence. Thus, our data highlights the key role of p53 in regulating the tumor reactive T cell response and that targeting this pathway could have potential translational significance in adoptive T cell therapy.

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Lentivirus-mediated shRNA interference of ghrelin receptor blocks proliferation in the colorectal cancer cells

Abstract

Ghrelin, an orexigenic peptide, acts via the growth hormone secretagogue receptor (GHSR) to stimulate the release of growth hormone. Moreover, it has a range of biological actions, including the stimulation of food intake, modulation of insulin signaling and cardiovascular effects. Recently, it has been demonstrated that ghrelin has a proliferative and antiapoptotic effects in cancers, suggesting a potential role in promoting tumor growth. However, it remains unknown whether GHSR contributes to colorectal cancer proliferation. In this study, the therapeutic effect of lentivirus-mediated short hairpin RNA (shRNA) targeting ghrelin receptor 1a (GHSR1a) was analyzed in colorectal cancer cell line SW480 both in vitro and in vivo. Our study demonstrated that ghrelin and GHSR1a are significantly upregulated in cancerous colorectal tissue samples and cell lines. In vitro, human colorectal cancer cell line SW480 with downregulation of GHSR1a by shRNA showed significant inhibition of cell viability compared with blank control (BC) or scrambled control (SC) regardless of the application of exogenous ghrelin. Furthermore, GHSR1a silencing by target specific shRNA was shown capable of increasing PTEN, inhibiting AKT phosphorylation and promoting the release of p53 in SW480 cells. In addition, the effects of GHSR1a knockdown were further explored in vivo using colorectal tumor xenograft mouse model. The tumor weights were decreased markedly in GHSR1α knockdown SW480 mouse xenograft tumors compared with blank control or negative control tumors. Our results suggested that the expression of GHSR1a is significantly correlated with the growth of colorectal cancer cells, and the GHSR1a knockdown approach may be a potential therapy for the treatment of colorectal cancer.

Downregulation of GHSR1a by short hairpin RNA (shRNA) technology inhibits the proliferation of colorectal cancer cell line and xenograft tumor through activation the signaling pathway of PTEN/PI3K/AKT.

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Palmitate-induced ER stress increases trastuzumab sensitivity in HER2/neu-positive breast cancer cells

Abstract

Background

HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment.

Methods

Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines.

Results

Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and CHOP-dependent apoptosis as well as a partial activation of the ER stress response network via XBP1 and ATF6. This response appears to be a general feature of HER2/neu-positive breast cancer cells but not cells that overexpress only HER2/neu. Exogenous palmitate reduces HER2 and HER3 protein levels without changes in phosphorylation and sensitizes HER2/neu-positive breast cancer cells to treatment with the HER2-targeted therapy trastuzumab.

Conclusions

Several studies have shown that HER2, FASN and fatty acid synthesis are functionally linked. Exogenous palmitate exerts its toxic effects in part through inducing ER stress, reducing HER2 expression and thereby sensitizing cells to trastuzumab. These data provide further evidence that HER2 signaling and fatty acid metabolism are highly integrated processes that may be important for disease development and progression.

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A rare case of extremely high counts of circulating tumor cells detected in a patient with an oral squamous cell carcinoma

Abstract

Background

Despite aggressive regimens, the clinical outcome of head and neck squamous cell carcinoma remains poor. The detection of circulating tumor cells could potentially improve the management of patients with disseminated cancer, including diagnosis, treatment strategies, and surveillance. Currently, CellSearch^® is the most widely used and the only Food and Drug Administration-cleared system for circulating tumor cells detection in patients with metastatic breast, colorectal, or prostate cancer. In most cases of head and neck squamous cell carcinoma, only low counts of circulating tumor cells have been reported.

Case presentation

A 56-year-old white male with no particular medical history, was diagnosed with a squamous cell carcinoma of oral cavity. According to the imaging results (computed tomography and ¹⁸F-fluorodeoxyglucose positron emission tomography / computed tomography) and panendoscopy, the TNM staging was classified as T4N2M0. A non-interruptive pelvimandibulectomy was conducted according to the multidisciplinary meeting advices and the postoperative observations were normal. The patient complained of a painful cervical edema and a trismus 6 weeks after the surgery. A relapse was found by computed tomography and the patient died two weeks later. The search for circulating tumor cells in peripheral venous blood by using the CellSearch^® system revealed a very high count compared with published reports at three time points (pre-operative: 400; intra-operative: 150 and post-operative day 7: 1400 circulating tumor cells). Of note, all detected circulating tumor cells were epidermal growth factor receptor negative.

Conclusion

We report here for the first time a rare case of oral squamous cell carcinoma with extremely high circulating tumor cells counts using the CellSearch^® system. The absolute number of circulating tumor cells might predict a particular phase of cancer development as well as a poor survival, potentially contributing to a personalized healthcare.

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Angiogenic cytokines and their influence on circulating tumour cells in sera of patients with the primary diagnosis of breast cancer before treatment

Abstract

Background

Circulating tumour cells (CTCs) have been found to be a prognostic marker for reduced disease free survival, breast cancer–specific survival, and overall survival before the start of systemic treatment.

Methods

A total of 200 patients' sera were included in this study, 100 patients being CTC positive and 100 patients being CTC negative. Matching criteria were histo-pathological grading, lymph node metastasis, hormone receptor status, TNM classification and survived breast cancer patients vs. deceased tumor associated patients. A multi cytokine/chemokine array was used to screen the sera for the angiogenic markers.

Results

Statistical significant correlation was exposed for sFlt1 values in regard to the CTC-Status. CTC negative patients displayed increased sFlt1 expression opposed to CTC positive breast cancer patients. Furthermore, significant enhanced PIGF values were also disclosed in CTC negative patients compared to patients being CTC positive. Analyzing the living patient collective we found significant differences in sFlt1 and PlGF values in regard to CTC negative and CTC positive patients.

Conclusion

Both vascular markers showed enhanced expression in the CTC negative patient collective. To continue, the collective graded G2 showed significantly enhanced sFlt1 expressions amongst patients with no CTCs. Moreover, the patient collective with no lymph node metastasis and CTC negativity indicated statistically significant increased sFlt1 values. A functional interaction of sFlt1 and PlGF was found, suggesting that their overexpression in tumour cells inhibits CTCs entering the peripheral blood. Furthermore, in regard to CTC negativity, sFlt1 and PlGF values may potentially serve as predictive markers.

Trial registration

The TRN of this study is NCT02181101 and the date of registration was the 4^th of June 2014. The study was retrospectively registered.

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MK-2206 sensitizes BRCA-deficient epithelial ovarian adenocarcinoma to cisplatin and olaparib

Abstract

Background

Platinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). Activation of the AKT pathway promotes platinum resistance while inhibition of AKT sensitizes chemoresistant cells. Patients with BRCA mutant EOC, and thus a defect in the homologous recombination (HR) repair pathway, demonstrate greater clinical response to platinum and olaparib therapy than patients with BRCA wild-type EOC. MK-2206, an allosteric inhibitor of AKT phosphorylation, sensitizes a variety of cell types to various anticancer agents and is currently undergoing phase II trials as monotherapy for platinum-resistant ovarian, fallopian tube, and peritoneal cancer. This study examines the differential effects of AKT inhibition with cisplatin and olaparib therapy in BRCA1/2-deficient versus wild-type EOC.

Methods

PEO1, a chemosensitive BRCA2-mutant serous ovarian adenocarcinoma, and PEO4, a reverted BRCA2-proficient line from the same patient after the development of chemotherapeutic resistance, were primarily used for the study. In PEO1, MK-2206 demonstrated moderate to strong synergism with cisplatin and olaparib at all doses, while demonstrating antagonism at all doses in PEO4.

Results

Baseline phospho-AKT activity in untreated cells was upregulated in both BRCA1- and 2-deficient cell lines. MK-2206 prevented cisplatin- and olaparib-induced AKT activation in the BRCA2-deficient PEO1 cells. We propose that BRCA-deficient EOC cells upregulate baseline AKT activity to enhance survival in the absence of HR. Higher AKT activity is also required to withstand cytotoxic agent-induced DNA damage, leading to strong synergism between MK-2206 and cisplatin or olaparib therapy in BRCA-deficient cells.

Conclusions

MK-2206 shows promise as a chemosensitization agent in BRCA-deficient EOC and merits clinical investigation in this patient population.

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Induction of artificial cancer stem cells from tongue cancer cells by defined reprogramming factors

Abstract

Background

The cancer stem cells (CSCs), a small subpopulation of cells in tumor are responsible for the tumor initiation, growth, recurrence and metastasis of cancer, as well as resistance of cancers to drugs or radiotherapy. CSCs are an important target for the development of novel strategies in cancer treatment. However, CSCs-targeted new anti-cancer drug discovery is currently hindered by the lack of easy and reliable methods for isolating, collecting and maintaining sufficient number of CSCs. Here, we examined whether introduction of defined reprogramming factors (Oct4, shp53, Sox2, Klf4, l-Myc and Lin28) into HSC2 tongue cancer cells could transform the HSC2 into HSC2 with CSCs properties.

Methods

We introduced the defined reprogramming factors into HSC2 tongue cancer cells via episomal vectors by electroporation method to generate transfectant cells. We investigated the malignant properties of the transfectant cells by cell proliferation assay, migration assay, wound healing assay, sphere formation assay, chemosensitivity and radiosensitivity assay in vitro; and also examined the tumorigenic potential of the transfectants in vivo.

Results

The transfectant cells (HSC2/hOCT3/4-shp53-F, HSC2/hSK, HSC2/hUL, HSC2/hOCT3/4-shp53-F + hSK, HSC2/hOCT3/4-shp53-F + hUL, HSC2/hSK + hUL, HSC2/hOCT3/4-shp53-F + hSK + hUL) displayed a malignant phenotype in culture and form tumors on the back of nude mice more efficiently than parental HSC2 and control HSC2/EGFP transfectant cells. They exhibited increased resistance to chemotherapeutic agents; 5-fluorouracil, cisplatin, docetaxel, trifluorothymidine, zoledronic acid, cetuximab, bortezomib and radiation when compared with HSC2 and HSC2/EGFP. Among all the transfected cells, HSC2/hOCT3/4-shp53-F + hSK + hUL cell containing all of the reprogramming factors showed the most aggressive and malignant properties and presented the highest number of spheres in the culture medium containing human recombinant fibroblast Growth Factor-2 (FGF-2) and epidermal Growth Factor (EGF).

Conclusion

These findings suggest that artificial cancer stem cells obtained by the induction of cellular reprogramming may be useful for investigating the acquisition of potential malignancy as well as screening the CSCs-targeting drugs.

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Microsatellite alteration and immunohistochemical expression profile of chromosome 9p21 in patients with sporadic renal cell carcinoma following surgical resection

Abstract

Background

Long-term prognostic significance of loss of heterozygosity on chromosome 9p21 for localized renal cell carcinoma following surgery remains unreported. The study assessed the frequency of deletions of different loci of chromosome 9p along with immunohistochemical profile of proteins in surgically resected renal cancer tissue and correlated this with long-term outcomes.

Methods

DNA was extracted from renal tumours and corresponding normal kidney tissues in prospectively collected samples of 108 patients who underwent surgical resection for clinically localized disease between January 2001 and December 2005, providing a minimum of 9 years follow-up for each participant. After checking quality of DNA, amplified by PCR, loss of heterozygosity (LOH) on chromosome 9p was assessed using 6 microsatellite markers in 77 clear cell carcinoma. Only 5 of the markers showed LOH (D9S1814, D9S916, D9S974, D9S942, and D9S171). Protein expression of p15(INK4b), p16(INK4a), p14(ARF), CAIX, and adipose related protein (ADFP) were demonstrated by immunostaining in normal and cancer tissues. Loss of heterozygosity for microsatellite analysis was correlated with tumour characteristics, recurrence free, cancer specific, and overall survival, including significance of immunohistochemical profile of protein expressions.

Results

The main deletion was found at loci telomeric to CDKN2A region at D9S916. There was a significant correlation between frequency of LOH stage (p = 0.005) and metastases (p = 0.006) suggesting a higher LOH for advanced and aggressive renal cell carcinoma. Most commonly observed LOH in the 3 markers: D9S916, D9S974, and D9S942 were associated with poor survival, and were statistically significant on multivariate analysis. Immunohistochemical expression of p14, p15, and p16 proteins were either low or absent in cancer tissue compared to normal.

Conclusions

Loss of heterozygosity of p921 chromosome is associated with aggressive tumours, and predicts cancer specific or recurrence free survival on long-term follow-up.

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Expression of circadian clock genes and proteins in urothelial cancer is related to cancer-associated genes

Abstract

Background

The purpose of this study was to evaluate invasive and metastatic potential of urothelial cancer by investigating differential expression of various clock genes/proteins participating in the 24 h circadian rhythms and to compare these gene expressions with transcription of other cancer-associated genes.

Methods

Twenty seven paired samples of tumour and benign tissue collected from patients who underwent cystectomy were analysed and compared to 15 samples of normal bladder tissue taken from patients who underwent cystoscopy for benign prostate hyperplasia (unrelated donors). Immunohistochemical analyses were made for clock and clock-related proteins. In addition, the gene-expression levels of 22 genes (clock genes, casein kinases, oncogenes, tumour suppressor genes and cytokeratins) were analysed by real-time quantitative PCR (qPCR).

Results

Considerable up- or down-regulation and altered cellular distribution of different clock proteins, a reduction of casein kinase1A1 (CSNK1A1) and increase of casein kinase alpha 1 E (CSNK1E) were found. The pattern was significantly correlated with simultaneous up-regulation of stimulatory tumour markers, and a down-regulation of several suppressor genes. The pattern was mainly seen in aneuploid high-grade cancers. Considerable alterations were also found in the neighbouring bladder mucosa.

Conclusions

The close correlation between altered expression of various clock genes and common tumour markers in urothelial cancer indicates that disturbed function in the cellular clock work may be an important additional mechanism contributing to cancer progression and malignant behaviour.

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Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma

Abstract

Hepatocellular carcinoma (HCC) and hepatic cholangiocarcinoma (CC) are the most aggressive malignancies with a poor prognosis in humans, and hepatic cholangiocarcinoma (CC) exhibits greater malignant behaviour. Yes-associated protein (YAP) is an important downstream target of the Hippo signalling pathway. As an oncogene, it plays a vital role in the occurrence and development of tumours. Our study focuses on the clinical significance of YAP protein expression in HCC and CC. Furthermore, we sought to explore the different survival rates between HCC and CC. A total of 137 patients with HCC and 122 with CC after resection were evaluated by immunohistochemistry for the expression of YAP. Our results showed that positive expression rates of YAP were more frequently noted in CC 67.2 % (82/122) than in HCC 56.9 % (78/137) (P = 0.024). High YAP expression in HCC and CC was significantly associated with tumour size (P < 0.001 and P = 0.019, respectively), liver cirrhosis (P = 0.002 and P = 0.009, respectively), vascular invasion (P = 0.047 and P = 0.018, respectively), multiplicity (P = 0.019 and P = 0.015, respectively), and intrahepatic metastasis (P = 0.015 and P = 0.047, respectively). Importantly, recurrence-free survival and disease-specific survival rates were lower in CC with high YAP expression than in HCC with high YAP expression (P < 0.001 and P < 0.001, respectively). Overall, high YAP expression was more frequently found in CC than in HCC, and YAP overexpression was associated with poor survival rates in patients with HCC and CC. Targeting YAP treatment requires further prospective investigations in larger patient populations.

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Fibronectin protects lung cancer cells against docetaxel-induced apoptosis by promoting Src and caspase-8 phosphorylation

Abstract

Fibronectin is involved in orchestrating many diverse cellular behaviors, including adhesion, invasion, differentiation, and proliferation and recently has also been shown to participate in the development of chemoresistance. In this study, we found that fibronectin expression was inversely correlated with clinical responses to docetaxel treatment in non-small cell lung cancer patients. Subsequently, we showed that fibronectin pretreatment could enhance cell viability and reduce apoptosis in docetaxel-treated lung cancer cells because fibronectin induced phosphorylated Src and caspase-8, rendering the later inactive, thus inhibiting docetaxel-induced apoptosis. The inhibition of apoptosis by fibronectin was found to be enhanced by Src overexpression and reversed by Src knockdown in lung cancer cells. Further investigation revealed that a downregulation of phospho-Src via treatment with a Src kinase inhibitor could also abolish fibronectin activity and recover docetaxel-induced apoptosis. Molecular studies revealed that this reversion was due to decreased phospho-Src levels rather than a reduction in total Src expression. Inhibition of phospho-Src reduced phospho-caspase-8 and promoted caspase-8 activity, restoring apoptosis following docetaxel and fibronectin co-treatment. Finally, xenografts experiments demonstrated that fibronectin promoted lung cancer cell proliferation during docetaxel treatment in vivo. Our findings indicate that fibronectin promotes Src and caspase-8 phosphorylation in lung cancer cells, which decreases caspase-8 activation and protects tumor cells from docetaxel-induced apoptosis. Therefore, the fibronectin/Src/caspase-8 pathway may play a crucial role in docetaxel resistance in lung cancer.

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The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide, and its incidence continues to increase. However, the mechanism underlying the development and progression of HCC remains unknown. The suppressor of cytokine signaling 2 (SOCS2) is a member of the SOCS family and influences the carcinogenesis of multiple types of tumors, but the biological roles of SOCS2 in HCC remain unclear. In this study, we found that SOCS2 expression was reduced in HCC tissues compared with matched noncancerous liver tissues. Moreover, decreased SOCS2 expression was significantly associated with the presence of intrahepatic metastasis and high histological grade in HCC patients. Colony formation assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that overexpression of SOCS2 or knockdown of endogenous SOCS2 did not significantly affect cell proliferation and tumorigenicity in HCC cells in vitro and in vivo. However, SOCS2 overexpression significantly inhibited the migration and invasion of HCC cells in vitro and inhibited metastasis in vivo. Consistent with these findings, the knockdown of endogenous SOCS2 enhanced migration and invasion in HCC cells in vitro. Our study demonstrated that SOCS2 inhibited human HCC metastasis, and SOCS2 might provide a new potential therapeutic strategy for treating HCC.

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PTP1B promotes aggressiveness of breast cancer cells by regulating PTEN but not EMT

Abstract

Metastasis is a complicated, multistep process and remains the major cause of cancer-related mortality. Exploring the molecular mechanisms underlying tumor metastasis is crucial for development of new strategies for cancer prevention and treatment. In this study, we found that protein tyrosine phosphatase 1B (PTP1B) promoted breast cancer metastasis by regulating phosphatase and tensin homolog (PTEN) but not epithelial-mesenchymal transition (EMT). By detecting PTP1B expression of the specimens from 128 breast cancer cases, we found that the level of PTP1B was higher in breast cancer tissues than the corresponding adjacent normal tissues. Notably, PTP1B was positively associated with lymph node metastasis (LNM) and estrogen receptor (ER) status. In vitro, disturbing PTP1B expression obviously attenuated cell migration and invasion. On the contrary, PTP1B overexpression significantly increased migration and invasion of breast cancer cells. Mechanistically, PTP1B knockdown upregulated PTEN, accompanied with an abatement of AKT phosphorylation and the expression of matrix metalloproteinase 2 (MMP2) and MMP7. Conversely, forced expression of PTP1B reduced PTEN and increased AKT phosphorylation as well as the expression of MMP2 and MMP7. Notably, neither EMT nor stemness of breast cancer cells was regulated by PTP1B. We also found that PTP1B acted as an independent prognostic factor and predicted poor prognosis in ER-positive breast cancer patients. Taken together, our findings provide advantageous evidence for the development of PTP1B as a potential therapeutic target for breast cancer, especially for ER-positive breast cancer patients.

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Mechanisms underlying the association between obesity and Hodgkin lymphoma

Abstract

A solid body of knowledge indicates that overweight and obese subjects are prone to develop cancer, aggressive disease, and death more than their lean counterparts. While obesity has been causally associated with various cancers, only a limited number of studies beheld the link with classical Hodgkin lymphoma (HL). Contemporary meta-analysis and prospective studies confirmed the association of body mass index with HL. Besides epidemiological evidence, excess adiposity is known to influence tumor behavior through adipokines, adipose-derived stem cell migration, and metabolism regulation, and by modulating immunoinflammatory response. Nevertheless, the obesity paradox has been described in few cancers. Considering that adipose tissue is an immunomodulatory organ, and that inflammation is the cornerstone of HL pathophysiology, the rationale for being causally related due to endocrine/paracrine interactions cannot be negligible. In this hypothesis-generating review, we explore the biologically plausible links between excess adiposity and HL in light of recent basic and clinical data, in order to create a basis for understanding the underlying mechanisms and foster applied research. The establishment of an association of excess adiposity with HL will determine public health preventive measures to fight obesity and eventually novel therapeutic approaches in HL patients.

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High expression of Rad51c predicts poor prognostic outcome and induces cell resistance to cisplatin and radiation in non-small cell lung cancer

Abstract

Rad51c is critical for homologous recombination repair and genomic stability and may play roles in tumorigenesis and cancer therapy. We investigated the expression level and clinical significance of Rad51c in non-small cell lung cancer (NSCLC) and determined the effect of Rad51c on NSCLC cell chemosensitivity and radiosensitivity. Rad51c expression was detected using immunohistochemistry and was higher in NSCLC patient samples than in adjacent normal tissues. Kaplan–Meier analysis revealed that high Rad51c expression was an independent predictor of short overall survival (OS) and disease-free survival (DFS) in NSCLC patients receiving chemotherapy and/or radiotherapy. Furthermore, Rad51c knockdown increased the killing effect of ionizing radiation (IR) and enhanced cisplatin-induced apoptotic cells in NSCLC cells by disrupting the repair of cisplatin- and IR-induced DNA damage. In addition, ectopic expression of Rad51c dramatically enhanced NSCLC cell resistance to cisplatin and radiotherapy. These findings suggest that increased expression of Rad51c may confer resistance to chemotherapy and/or radiotherapy of NSCLC, and also be an independent prognostic factor for patient outcome. Therefore, targeting Rad51c may represent an improved therapeutic strategy for NSCLC patients with locally advanced disease.

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Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma

Abstract

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Fibronectin protects lung cancer cells against docetaxel-induced apoptosis by promoting Src and caspase-8 phosphorylation

Abstract

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The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma

Abstract

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High expression of Rad51c predicts poor prognostic outcome and induces cell resistance to cisplatin and radiation in non-small cell lung cancer

Abstract

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Low-dose brachytherapy for early stage penile cancer: a 20-year single-institution study (73 patients)

Abstract

Purpose/objectives

The aim of this study is to analyze the results of exclusive interstitial brachytherapy (IBT) as a conservative approach in the treatment of penile cancer confined to the glans or the shaft with long-term follow-up in a single institution.

Materials/methods

Between July 1992 and November 2013, 73 consecutive patients with non-metastatic invasive penile cancer were treated by Low dose rate (LDR) IBT in our institution. The localization of the primary lesion was glands in 67 patients (91.8 %) and shaft in 6 patients (8.2 %). All 73 patients presented with squamous cell carcinoma with grades of differentiation as follows: 34 patients with grade 1 (44.7 %), 9 patients with grade 2 (11.8 %), 9 patients with grade 3 (11.8 %) and 21 patients unknown (28.8 %). Six patients (7.8 %) presented with in situ carcinoma, 55 patients (75,3 %) presented with T1, 11 patients (15 %) presented with T2, and one patient (1.3 %) presented with Tx. Inguinal nodal dissection was performed in 29 patients (38.2 %); 13 patients (17.8 %) presented with histologically confirmed positive ganglion. After circumcision, IBT was performed using a hypodermic needle. The median dose delivered was 60 Gy (range, 40 to 70 Gy). The median activity of the iridium-192 wire was 1.12 mCi/cm, and the median reference isodose rate was 0.4 Gy/h (range, 0.2–1.2). Patients with histological inguinal metastases received external beam radiotherapy to the selected inguinal affected area with a median dose of 45 Gy (30–55 Gy).

Results

The median follow-up time was 51.8 months (range 34.4 to 68.7). The 5-year overall survival was 82.0 %, with eight deaths from cancer and five non-cancer-related deaths. Disease-specific survival was 91.4 %, relapse-free survival was 64.4 %, and local relapse-free survival as 74 %. Total or partial penile preservation was 87.9 % at 5-years. Complications rates at 5 years were 6.6 % urethral stenosis (five patients), two patients (2.6 %) with pain related to sexual intercourse and four patients (5.3 %) with dysuria grade 2. Five patients (6.8 %) required penile amputation for necrosis.

Conclusions

IBT provides good local control with organ preservation, excellent tolerance and low complication rates in early-stage penile cancers.

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Resistance training concomitant to radiotherapy of spinal bone metastases – survival and prognostic factors of a randomized trial

Abstract

Purpose

To compare the effects of resistance training versus passive physical therapy on bone survival in the metastatic bone during radiation therapy (RT) as combined treatment in patients with spinal bone metastases. Secondly, to evaluate overall survival and progression-free-survival (PFS) as well as to quantify prognostic factors of bone survival after combined treatment.

Methods

In this randomized trial 60 patients were allocated from September 2011 until March 2013 into one of the two groups: resistance training (group A) or passive physical therapy (group B) with thirty patients in each group during RT. We estimated patient survival using Kaplan-Meier survival method. The Wald-test was used to evaluate the prognostic importance of pathological fracture, primary site, Karnofsky performance status, localization of metastases, number of metastases, and cerebral metastases.

Results

Median follow-up was 10 months (range 2–35). Bone survival showed no significant difference between groups (p = .303). Additionally no difference between groups could be detected in overall survival (p = .688) and PFS (p = .295). Local bone progression was detected in 16.7 % in group B, no irradiated bone in group A showed a local progression over the course (p = 0.019). In univariate analysis breast cancer, prostate cancer, and the presence of cerebral metastases had a significant impact on bone survival in group B, while no impact could be demonstrated in group A.

Conclusions

In this group of patients with spinal bone metastases we were able to show that guided resistance training of the paravertebral muscles had no essential impact on survival concomitant to RT. Importantly, no local bone progression in group A was detected, nevertheless no prognostic factor for combined treatment could be evaluated.

Trial registration

Clinical trial identifier NCT 01409720. Registered 8 February 2011.

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Partner-Aided Skin Exams Increase Early Detection of New Melanomas

People who have previously been treated for melanoma—and are therefore at high risk for developing a second melanoma—can team up with a spouse, family member, or a friend and be trained to find new melanomas successfully, a new clinical trial showed.

In the trial, patients and their skin-check partners who received training in how to find and track suspicious moles over time found substantially more early-stage melanomas than pairs who only received reminders from their doctors to perform regular skin self-examinations.

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Candidate microRNAs as biomarkers of thyroid carcinoma: a systematic review, meta-analysis, and experimental validation

Abstract

Thyroid cancer is one of the most common carcinomas of the endocrine system with an increasing incidence. A growing number of studies have focused on the diagnostic and prognostic values of dysregulated microRNAs (miRNAs) in thyroid carcinoma. However, differences in the measurement platforms, variations in lab protocols, and small sample sizes can make gene profiling data incomparable. A meta-review of the published studies that compared miRNA expression data of thyroid carcinoma and paired normal tissues was performed to identify potential miRNA biomarkers of thyroid carcinoma with the vote-counting strategy. Two hundred and thirty-six aberrantly expressed miRNAs were reported in 19 microRNA expression profiling studies. Among them, 138 miRNAs were reported in at least two studies. We also provided a meta-signature of differentially expressed miRNAs between individual histological types of thyroid carcinoma and normal tissues. The experimental validation with qRT-PCR analysis verified that the profiles identified with the meta-review approach could effectively discriminate papillary thyroid carcinoma tissues from paired noncancer tissues. The meta-review of miRNA expression profiling studies of thyroid carcinoma would provide information on candidate miRNAs that could potentially be used as biomarkers in thyroid carcinoma.

We provided a meta-signature of differentially expressed miRNAs between individual histological types of thyroid carcinoma and normal tissues.

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Evaluation of in vivo antitumor effects of low-frequency ultrasound-mediated miRNA-133a microbubble delivery in breast cancer

Abstract

MicroRNAs (miRNAs), as a novel class of small noncoding RNAs, have been identified as important transcriptional and posttranscriptional inhibitors of gene expression. Ultrasound-targeted microbubble destruction (UTMD) is a noninvasive method for microRNA delivery. We aimed to investigate the effect of UTMD of miR-133a on breast cancer treatment. It has been reported that miRNA-133a is involved in various cancers. miR-133a was lowly expressed in breast cancer tissues and breast cancer cell lines MCF-7 and MDA-MB-231. The miR-133a expression was significantly upregulated under exogenous miRNA-133a treatment in MCF-7 and MDA-MB-231 cells analyzed by qRT-PCR. Exogenous miR-133a promoted the cell proliferation as determined by diphenyl tetrazolium bromide (MTT) assay and 5-ethynyl-2′-deoxyuridine (EdU) staining. Epidermal growth factor receptor (EGFR) expression and Akt phosphorylation were significantly suppressed after miR-133a transfection by western blot detection. We prepared the miR-133a-microbubble and injected it into breast cancer xenografts. The miR-133a-microbubble injection prolonged miR-133a circulatory time by detecting the amount of miRNA-133a in the plasma. No significant toxicity was observed on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at liver and albumin, blood urea nitrogen, or creatine kinase levels at kidney after miR-133a-microbubble injection. The tumor size of miR-133a-microbubble-injected mice was smaller than that of the control group. Furthermore, the delivery efficiency of miR-133a with low frequency was higher than that with common frequency. miR-133a suppressed cell proliferation by suppressing the expression of EGFR and the phosphorylation of Akt. UTMD of miR-133a inhibited the tumor growth and improved the survival rate in breast cancer mice. Our study provides new evidence that UTMD of miRNA is a promising platform for breast cancer therapy.

miR-133a suppressed cell proliferation by suppressing the expression of epidermal growth factor receptor (EGFR) and the phosphorylation of Akt. Ultrasound-targeted microbubble destruction (UTMD) of miR-133a inhibited the tumor growth and improved the survival rate in breast cancer mice. Our study provides new evidence that UTMD is a promising platform for miRNA delivery, with proper ultrasound frequency choice.

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Characterization of the T-cell receptor beta chain repertoire in tumor-infiltrating lymphocytes

Abstract

Tumor-infiltrating lymphocytes (TILs) are direct effectors of tumor immunity, and their characterization is important for further development of immunotherapy. Recent advances in high-throughput sequencing technologies have enabled a comprehensive analysis of T-cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, which may provide information of therapeutic importance. We developed a high-fidelity target sequencing method with the ability for absolute quantitation, and performed large-scale sequencing of TCR beta chain (TCRB) CDR3 regions in TILs and peripheral blood lymphocytes (PBLs). The estimated TCRB repertoire sizes of PBLs from four healthy individuals and TILs from four colorectal cancer tissue samples were 608,664–1,003,098 and 90,228–223,757, respectively. The usage of J- and V-regions was similar in PBLs and TILs. Proportions of CDR3 amino acid (aa) sequences occupying more than 0.01% of the total molecular population were 0.33–0.43% in PBLs and 1.3–3.6% in TILs. Additional low coverage sequencing of 15 samples identified five CDR3 aa sequences that were shared by nine patients, one sequence shared by 10 patients, and one sequence shared by 12 patients. The estimated size of the TCRB repertoire in TILs was significantly smaller than that in PBLs. The proportion of abundant species (>0.01%) in TILs was larger than that in PBLs. Shared CDR3 aa sequences represent a response to common antigens, and the identification of such CDR3 sequences may be beneficial in developing clinical biomarkers.

Recent advances in high-throughput sequencing technologies enabled a comprehensive analysis of immunorepertoires, which might provide information of therapeutic importance. We developed a high-fidelity target sequencing method with the ability for absolute quantitation and performed large-scale sequencing of T-cell receptor beta chain complementarity-determining region 3 in tumor-infiltrating lymphocytes.

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Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)

Abstract

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74–1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05–2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02–2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67–1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68–13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31–2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88–1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32–1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab.

Plasma samples collected during the randomized phase II trial CALGB 80203 comparing FOLFOX or FOLFIRI chemotherapy with or without cetuximab in metastatic colorectal cancer (mCRC) were assayed for levels of six candidate biomarker proteins [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. High EGF was predictive of lack of benefit from cetuximab in KRAS WT patients and predictive of benefit in KRAS Mut patients. High HER3 was predictive of lack of benefit in all patients and CD73 was predictive of benefit in KRAS WT patients. These data implicate HER3 signaling and inflammatory signaling in the biological response to cetuximab.

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miR-302b regulates cell cycles by targeting CDK2 via ERK signaling pathway in gastric cancer

Abstract

To investigate the molecular mechanism of miR-302b in the regulation of cell proliferation and cell cycle regulation in gastric cancer. Samples of tumor and adjacent normal tissues were collected from 30 gastric cancer patients. Bioinformatics and the dual luciferase report were used for verification of the relationship between miR-302b expression and cyclin-dependent kinase 2 (CDK2). RT-PCR and western blot were used to examine CDK2 mRNA and protein levels. The impacts of miR-302b on CDK2 expression and extracellular signal-regulated kinase (ERK) signaling pathway were assessed in cells transfected with miR-302b analogs and CDK2 overexpression carrier, respectively. We used 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) to assay gastric cancer cell growth after transfection, flow cytometry to analyze cell cycle. Compared with normal tissues, miR-302b expression was significantly lower in gastric cancer tissues, which was significantly related to lymph node metastasis, metastasis distance, and TNM staging. miR-302b expression was increased in miR-302b mimics transfected cells and was significantly decreased in miR-302b inhibitors transfected cells. CDK2 is a target gene of miR-302b. Decreased miR-302b and increased CDK2 expressions can significantly promote proliferation and G1/S phase transformation in gastric cancer. miR-302b promoted the proliferation of gastric cancer cells through upregulation of CDK2, thereby inhibiting ERK pathway, which can in turn inhibit the promoting ability of miR-302b on proliferation. The upregulation of miR-302b reduced the expression of CDK2, and inhibited ERK signaling pathway, thereby inhibiting cell proliferation and G1/S phase conversion rate. Therefore, miR-302b provides new perspectives for research of cell regulation and proliferation in gastric cancer, and new targets for gastric cancer diagnosis and treatment.

We first showed that miR-302b regulates gastric cancer cell cycle through CDK2; We first examined the links between miR-302b and extracellular signal-regulated kinase (ERK) signaling pathway; miR-302b expression was significantly decreased in gastric cancer cells.

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A novel hedgehog inhibitor iG2 suppresses tumorigenesis by impairing self-renewal in human bladder cancer

Abstract

Tumor recurrence is still a major challenge for clinical treatment of bladder cancer. Cumulative evidences indicate cancer stem cells (CSCs) contribute to drug resistance and leave a putative source for disease relapse. Identifying novel agents targeting CSCs may represent a new paradigm in the therapy of bladder cancer. Here, we separated a novel hedgehog (Hh) inhibitor, iG2, from streptomyces roseofulvus, which dramatically blocked the activation of Gli2 in bladder cancer cells. The iG2 strongly repressed the growth of cancer cells rather than the peri-tumor stroma cells. Attenuated proliferation and enhanced apoptosis of tumor cells were observed upon iG2 stimulation. Furthermore, iG2 reduced the self-renewal ability of bladder CSCs as well as the tumor formation. Collectively, iG2 is potentially used as a novel therapeutic agent for bladder cancer by targeting self-renewal through inhibiting Hh pathway.

iG2 is a novel hedgehog inhibitor which dramatically blocked the activation of Gli2 in bladder cancer cells. The iG2 strongly repressed the growth, attenuated proliferation and reduced the self-renewal ability of bladder CSCs. iG2 is potentially used as a novel therapeutic agent for bladder cancer by targeting self-renewal through inhibiting Hh pathway.

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The genetic variations in DNA repair genes ERCC2 and XRCC1 were associated with the overall survival of advanced non-small-cell lung cancer patients

Abstract

It was reported that DNA repair can confer cancer cell resistance to therapeutic treatments by activating antiapoptotic cellular defense. We hypothesized that genetic variants of DNA repair genes may be associated with lung cancer prognosis. Seventeen tagging single-nucleotide polymorphism (tagSNPs) selected from 12 DNA repair genes were genotyped in 280 advanced non-small-cell lung cancer (NSCLC) patients by TaqMan assay. The associations of these SNPs and overall survival of advanced NSCLC patients were investigated. Advanced NSCLC patients carrying ERCC2 rs50872 CT+TT genotypes had significantly longer median survival time (MST) and decreased death risk than patients with rs50872 CC genotype [log-rank P = 0.031; adjusted HR(95% CI) = 0.73 (0.55–0.98), P = 0.033]. These effects were mainly seen among younger patients (≤65 years old) [HR(95% CI) = 0.57 (0.37–0.87), P = 0.010], patients without surgery [HR(95% CI) = 0.68 (0.47–0.98), P = 0.036] but with chemotherapy [HR(95% CI) = 0.64 (0.46–0.91), P = 0.012] or radiotherapy [HR(95% CI) = 0.58 (0.38–0.89), P = 0.013]. Meanwhile, compared to advanced NSCLC patients with rs25487 GG genotype, patients carrying XRCC1 rs25487 GA+AA genotypes had significantly shorter MST (MST = 11.7 vs. 16.7, log-rank P = 0.048). In addition, advanced NSCLC patients carrying the ERCC2 rs50872 CC in combination with XRCC1 rs25487 GA+AA genotype had the shortest MST (11.2 month) and highest death risk [HR(95% CI) = 1.70 (1.15–2.52), P = 0.008] when compared with those carrying rs50872 CT+TT and rs25487 GG genotype (MST = 22.0 month). The ERCC2 rs50872 T allele was associated with favorable but XRCC1 rs25487 A allele with bad survival for advanced NSCLC in Chinese population, which may offer novel biomarkers for predicting clinical outcomes.

The ERCC2 rs50872 T allele was associated with favorable advanced non-small-cell lung cancer (NSCLC) survival. The XRCC1 rs25487 A allele was associated with bad advanced NSCLC survival. ERCC2 rs50872 CC in combination with XRCC1 rs25487 GA+AA had the worst survival.

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Serum NSE, MMP-9 and HER2 extra-cellular domain are associated with brain metastases in metastatic breast cancer patients: Predictive biomarkers for brain metastases?

Abstract

Breast cancer (BC) is the second most common cause of brain metastases (BM). Predictive factors for BM have been widely studied in metastatic BC; however, there is no known serum tumor marker to accurately predict BM. Elevated serum S100ß protein and Neuron-Specific Enolase (NSE) could reflect the brain damages induced by BM. Matrix Metalloproteinase 9 (MMP-9) is involved in tumor invasion and metastatic dissemination, including BM. Also, HER2-amplified BC were shown to have a particular tropism for central nervous system (CNS). This study evaluated the correlation of these biomarkers with the presence of BM in metastatic BC patients.

In this case-control study, 88 consecutive metastatic BC patients with BM (BM group) treated in our institution (2008-2015) were retrospectively selected, based on the availability of frozen serum samples for tumor marker determination. Patients were matched by age, tumor biology and number of previous metastatic chemotherapy lines to 162 metastatic BC patients without CNS involvement (control group).

Serum NSE, MMP-9 and HER2 extra-cellular domain (ECD) levels were significantly higher in the BM group (p=0.0051, p=0.0062 and p=0.0057, respectively). In multivariate analysis, serum HER2 and MMP-9 levels accurately discriminated patients with BM: odds-ratios 4.4 (p<0.001; 95%CI: 1.9-9.6) for HER2 ECD and 3.5 (p=0.005; 95%CI: 1.5-8.4) for MMP-9. In multivariate analysis, HER2 ECD and NSE serum levels were independent prognostic factors in patients with BM.

Serum HER2 ECD and MMP-9 appear to be associated with BM in metastatic BC patients. Their predictive value for BM still needs to be evaluated in further prospective studies. This article is protected by copyright. All rights reserved.

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The Potential Diagnostic Value of Serum microRNA Signature in Patients with Pancreatic Cancer

Abstract

Biomarkers for early diagnosis of patients with pancreatic cancer (PC) are needed. Our aim was to identify panels of miRNAs in serum in combination with CA 19-9 for use in the diagnosis of PC. Four hundred seventeen patients with PC were included prospectively from Denmark (n=306) and Germany (n=111). Controls included 59 patients with chronic pancreatitis (CP) and 248 healthy subjects (HS). MiRNAs were analyzed in pre-treatment serum samples from 3 cohorts: discovery cohort (754 human miRNAs, TaqMan® Human MicroRNA assay, Applied Biosystem; PC n=133, controls n=72); training cohort (34 miRNAs, real-time qPCR using the Fluidigm BioMarkTM System; PC n=198, controls n=184); validation cohort (13 miRNAs, real-time qPCR using the Fluidigm BioMarkTM System; PC n=86, controls n=51). We found that 34 miRNAs in serum from PC patients in the discovery cohort were expressed differently than in controls. These miRNAs were tested in the training cohort, and 4 diagnostic panels were constructed that included 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, -191, -323.3p, -345, -483.5p). Diagnostic accuracy of detecting PC in the training cohort was AUC (index I 0.85; II 0.87; III 0.85; IV 0.95; CA 19-9 0.93); specificity (I 0.71; II 0.76; III 0.66; IV 0.90 (fixed sensitivity at 0.85); CA 19-9 0.93). Combining serum CA 19-9 and index II best discriminated stages I and II PC from HS (AUC 0.93 (0.90–0.96); sensitivity 0.77 (0.69–0.84); specificity 0.94(0.90–0.96); accuracy 0.88 (0.84–0.91)). In conclusion, we identified 4 diagnostic panels based on 5 or 12 miRNAs in serum that could distinguish patients with PC from HS and CP. This article is protected by copyright. All rights reserved.

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Resistance training concomitant to radiotherapy of spinal bone metastases – survival and prognostic factors of a randomized trial

To compare the effects of resistance training versus passive physical therapy on bone survival in the metastatic bone during radiation therapy (RT) as combined treatment in patients with spinal bone metastases...

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Low-dose brachytherapy for early stage penile cancer: a 20-year single-institution study (73 patients)

Erratum to: High Jagged1 expression is associated with poor outcome in primary glioblastoma

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Evolution of gastric surgery techniques and outcomes

Surgical management of gastric cancer improves survival. However, for some time, surgeons have had diverse opinions about the extent of gastrectomy. Researchers have conducted many clinical studies, making slo...

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