Different Genotype of rs3130932 Single Nucleotide Polymorphism Between Gastric Cancer Patients and Normal Subjects

Abstract

Purpose

Octamer binding transcription factor B gene (OCT4) is responsible for development and self-renewal maintenance of embryonic stem cells. The rs3130932 single nucleotide polymorphism (SNP) may play a role in tumor genesis. Because of high prevalence of gastric cancer in north of Iran, this study was investigated role of rs3130932 polymorphism and stomach cancer.

Methods

Blood samples were collected from 100 informed gastric cancer patients and 100 age and sex-matched healthy individuals, and were genotyped for the presence of rs3130932G allele by ssp PCR.

Results

The mean age of participant (n = 200) was 67.83 ± 10.878 years. In genotyping and allelic analysis, TG genotype increased 66.147 times more likely to develop stomach cancer than the TT genotype, and disease risk increases 140.496 times more in GG genotype in comparison with TT genotype.

Conclusion

This study clearly emphasis on different genetic profile in this population and show that the rs3130932G allele and odds of gastric cancer are related to each other in northern of Iran.

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Bivalent BET bromodomain inhibitor AZD5153

The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small-molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of Acute Myeloid Leukemia (AML), Multiple Myeloma (MM), and Diffuse Large B-cell Lymphoma (DLBCL). The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly impacts transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This report establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides rationale for clinical development in hematologic malignancies.

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Inhibiting Scaffold-MAPK in Multiple Myeloma

Despite improved outcomes in newly diagnosed multiple myeloma (MM), virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory MM patients, but its biological consequences are not fully understood. Self-renewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse and we examined the role of RAS/MAPK activation on MM self-renewal by targeting IQ motif-containing GTPase activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of MM cell lines and primary clinical specimens in vitro as well as tumor initiating cell frequency in immunodeficient mice. During MM progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.

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Novel covalent EGFR TKI overcomes T790M-mediated resistance

AC0010 is a pyrrolopyrimidine-based irreversible epidermal growth factor receptor (EGFR) inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR active and T790M mutations with up to 298-fold increase in potency compared to wild-type EGFR. In a xenografte model, oral administration of AC0010 at daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR active and T790M mutations for over 143 days with no weight loss. Three major metabolites of AC0010 were tested and showed no wild-type EGFR inhibition and off-target effects such as inhibition of IGF-1R. AC0010 is safe in non-small cell lung cancer (NSCLC) patients at the dose range between 50 mg and 550 mg once per day and no hyperglycemia and other severe adverse effects were detected such as grade 3 QT prolongation. The objective responses were observed in NSCLC patients with EGFR T790M mutation.

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Proteoglycans as target for therapy of chondrosarcoma

To date, surgery remains the only option for the treatment of chondrosarcoma (CHS), which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognostic, improving the management of CHS still remains a challenge. Our team develops an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan(PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by Surface Plasmon Resonance. In the orthotopic model of swarm rat CHS, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabelled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [3H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA active targeting of CHS. The antitumoral effects were characterized by tumor volume assessment, in vivo 99mTc-NTP 15-5 scintigraphic imaging of PG, 1H-HRMAS NMR spectroscopy and histology. The conjugation of a QA function to Mel doesn't hampered its in vivo efficiency and strongly improves tolerability of Mel leading to a significant decrease of side effects (hematological analyses and body weight monitoring). Thus QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with CHS.

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Patient-derived xenograft models of ovarian cancer

Purpose: Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with high rates of recurrence and eventual resistance to cytotoxic chemotherapy. Model systems that allow for accurate and reproducible target discovery and validation are needed to support further drug development in this disease. Experimental Design: Clinically-annotated patient-derived xenograft (PDX) models were generated from tumor cells isolated from the ascites or pleural fluid of patients undergoing clinical procedures. Models were characterized by immunohistochemistry and by molecular analyses. Each PDX was luciferized to allow for reproducible in vivo assessment of intraperitoneal tumor burden by bioluminescent imaging (BLI). Plasma assays for CA125 and human LINE-1 were developed as secondary tests of in vivo disease burden. Results: 14 clinically annotated and molecularly characterized luciferized ovarian PDX models were generated. Luciferized PDX models retain fidelity to both the non-luciferized PDX and the original patient tumor, as demonstrated by immunohistochemistry, array CGH, and targeted and whole-exome sequencing analyses. Models demonstrated diversity in specific genetic alterations and activation of PI3K signaling pathway members. Response of luciferized PDX models to standard of care therapy could be reproducibly monitored by BLI or plasma markers. Conclusions: We describe the establishment of a collection of 14 clinically annotated and molecularly characterized luciferized ovarian PDX models in which orthotopic tumor burden in the intraperitoneal space can be followed by standard and reproducible methods. This collection is well-suited as a platform for proof-of-concept efficacy and biomarker studies and for validation of novel therapeutic strategies in ovarian cancer.

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A tumor-targeting c-Met ADC

Purpose: Experimental Design:ADC ABBV-399 was generated with the c-Met targeting antibody, ABT-700. Anti-tumor activity was evaluated in cancer cells with overexpressed c-Met or amplified MET and in xenografts including patient-derived xenograft (PDX) models and those refractory to other c-Met inhibitors. The correlation between c-Met expression and sensitivity to ABBV-399 in tumor and normal cell lines was assessed to evaluate risk of on target toxicity. Results: A threshold level of c-Met expressed by sensitive tumor but not normal cells is required for significant ABBV-399-mediated killing of tumor cells. Activity extends to c-Met or amplified MET cell line and PDX models where significant tumor growth inhibition and regressions are observed. ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard of care chemotherapy. Results:A threshold level of c-Met expressed by sensitive tumor but not normal cells is required for significant ABBV-399-mediated killing of tumor cells. Activity extends to c-Met or amplified MET cell line and PDX models where significant tumor growth inhibition and regressions are observed. ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard of care chemotherapy. Conclusions:ABBV-399 represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met-overexpressing tumor cells enabling cell killing regardless of reliance on MET signaling. ABBV-399 has progressed to a Phase 1 study where it has been well tolerated and has produced objective responses in c-Met expressing non small cell lung cancer (NSCLC) patients.

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Pancreatic Cysts

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are surgically treatable cancer precursors, if high-risk features can be identified. Analysis of proteins and genes in cyst fluid helps diagnostically, but prior biomarkers had limited ability to detect high-risk cases. Cyst fluid telomerase activity may be a useful biomarker for high-risk IPMNs.

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Rationale of an economically driven PD1 biomarker development in lung cancer—an academic dilemma

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Sarcopenia predicts 1-year mortality in elderly patients undergoing curative gastrectomy for gastric cancer: a prospective study

Abstract

Purpose

One-year mortality is vital for elderly oncologic patients undergoing surgery. Recent studies have demonstrated that sarcopenia can predict outcomes after major abdominal surgeries, but the association of sarcopenia and 1-year mortality has never been investigated in a prospective study.

Methods

We conducted a prospective study of elderly patients (≥65 years) who underwent curative gastrectomy for gastric cancer from July 2014 to July 2015. Sarcopenia was determined by the measurements of muscle mass, handgrip strength, and gait speed. Univariate and multivariate analyses were used to identify the risk factors associated with 1-year mortality.

Results

A total of 173 patients were included, in which 52 (30.1 %) patients were identified as having sarcopenia. Twenty-four (13.9 %) patients died within 1 year of surgery. Multivariate analysis showed that sarcopenia was an independent risk factor for 1-year mortality. Area under the receiver operating characteristic curve demonstrated an increased predictive power for 1-year mortality with the inclusion of sarcopenia, from 0.835 to 0.868. Solely low muscle mass was not predictive of 1-year mortality in the multivariate analysis.

Conclusions

Sarcopenia is predictive of 1-year mortality in elderly patients undergoing gastric cancer surgery. The measurement of muscle function is important for sarcopenia as a preoperative assessment tool.

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Prognosis of mucinous and signet-ring cell colorectal cancer in a population-based cohort

Abstract

Purpose

Besides classical colorectal adenocarcinomas (AC), mucinous adenocarcinomas (MAC) and signet-ring cell carcinomas (SC) occur. Controversy remains regarding their prognostic role. Aim of this study was to define prognostic and histopathological specifications of mucinous and signet-ring cell colorectal cancer.

Methods

A total of 28,056 patients with AC, MAC, and SC between 1998 and 2012 in the catchment area of the Munich Cancer Registry were analyzed. Time to locoregional recurrence and distant recurrence was calculated by cumulative incidence. Survival was analyzed by the Kaplan–Meier method, calculation of relative survival, and Cox proportional hazards regression.

Results

AC occurred in 25,172 patients (90 %), MAC in 2724 (9.7 %), and SC in 160 (0.6 %). AC were less frequently localized in the proximal colon (34 %) compared to MAC (57 %, p < 0.001) and SC (76 %, p < 0.001). Both, MAC and SC had higher T, N, and M categories, lymphatic invasion, and worse grading (p < 0.001 for each). There were significant differences regarding the 10-year cumulative incidence of locoregional recurrence (p < 0.001), and distant recurrence (p < 0.001). For AC, the 5-year overall survival was 59 % (95 % confidence interval 58.0; 59.3), for MAC 52 % (50.2; 54.2), and for SC 40 % (32.1; 48.5; p < 0.001). However, MAC or SC did not remain independent prognostic factors for overall survival compared to AC upon multivariable analysis (p = 0.981).

Conclusion

This large cohort reveals specific histopathological and recurrence patterns for patients with colorectal AC, MAC, and SC. MAC and SC are diagnosed at more advanced tumor stages and therefore entail reduced survival rates.

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Knockdown of Hypoxia-Inducible Factor 1{alpha} Improved the Efficacy of Low-Dose Metronomic Chemotherapy of Paclitaxel in Human Colon Cancer Xenografts

Low-dose metronomic chemotherapy represents a new strategy for solid tumor treatments with a strong antiangiogenic activity and few side effects. However, low-dose metronomic therapy alone is not always as effective as traditional chemotherapy on eradication of tumor. On the contrary, low-dose metronomic in some cases could stimulate tumor growth due to hypoxia of tumor cells induced during therapy. Our study aimed to investigate whether knockdown of hypoxia-inducible factor-1α expression in tumor cell could facilitate low-dose metronomic therapy with paclitaxel for human colon cancer. Human colon cancer cell line (HT-29) stably transfected with specific short hairpin RNAs silencing hypoxia-inducible factor-1α exhibited marked attenuation of hypoxia-induced expression of the target genes such as vascular endothelial growth factor, glucose transporter 1, and P-glycoprotein. Compared with HT-29-c xenograft tumor model established by subcutaneous injection of HT-29 cells stably transfected with scrambled control short hairpin RNA, HT-29-ih xenograft tumor model showed more significant and long-lasting antitumor responses of empirical metronomic paclitaxel regimens, accompanied by drastic angiogenesis decrease and neglectable toxicity. All these data indicated that the combination of paclitaxel low-dose metronomic therapy with hypoxia-inducible factor-1α knockdown might provide a potent battle against colon cancer.

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New on NCI’s Websites for August 2016

NCI's cancer information products are constantly evolving and growing, so periodically we provide updates on new content of interest to the cancer community.

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Extensive heterotopic gastric mucosa of the small intestine: imaging with 99m Tc-sodium pertechnetate SPECT/CT enterography

Abstract

Extensive heterotopic gastric mucosa of the small intestine is a rare, but potentially life-threatening condition characterized by multifocal or long-segment heterotopic gastric mucosa within the bowel lumen that is often associated with other anomalies including malrotation and annular pancreas. Although the imaging findings are characteristic, this entity may be unrecognized due to its unusual imaging appearance and rarity. CT or MR enterography and ^99mTc-sodium pertechnetate scintigraphy can provide complementary information that enables specific diagnosis and accurate assessment of disease extent. We present a case of extensive heterotopic gastric mucosa of the small intestine imaged by simultaneous, combined ^99mTc-sodium pertechnetate single photon-emission computed tomography (SPECT)/CT enterography to both familiarize the reader with the condition and describe an imaging strategy that enables specific diagnosis and assists with treatment planning.

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The Unexpected Roles of Aurora A Kinase in Gliobastoma Recurrences

Abstract

The main obstacle for the cure of glioblastoma (GBM) is systematic tumor recurrence after treatment. More than 90 % of GBM tumors are indeed recurrent within 5 years after diagnosis and treatment. We urgently need new therapies to specifically address these deadly relapses. A major advance in the understanding of GBM recurrence is the identification of GBM-Initiating Cells (GIC), characterized by their abilities for self-renewal, multilineage differentiation, and proliferation. It appears that these features of GIC could be modulated by the mitotic kinase Aurora A (AurA). Indeed, besides its role in mitosis, AurA has recently been identified to regulate alternative functions like cell polarity, asymmetric cell division, and epithelial to mesenchymal transition. All these properties may help explain GBM therapeutic resistance and recurrence. In this review, we make the hypothesis that AurA could significantly contribute to GBM recurrences and we focus on the possible roles of AurA in GIC.

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Interspecific correlation between red blood cell mitochondrial ROS production, cardiolipin content and longevity in birds

Abstract

Mitochondrial respiration releases reactive oxygen species (ROS) as by-products that can damage the soma and may in turn accelerate ageing. Hence, according to "the oxidative stress theory of ageing", longer-lived organisms may have evolved mechanisms that improve mitochondrial function, reduce ROS production and/or increase cell resistance to oxidative damage. Cardiolipin, an important mitochondrial inner-membrane phospholipid, has these properties by binding and stabilizing mitochondrial inner-membrane proteins. Here, we investigated whether ROS production, cardiolipin content and cell membrane resistance to oxidative attack in freshly collected red blood cells (RBCs) are associated with longevity (range 5–35 years) in 21 bird species belonging to seven Orders. After controlling for phylogeny, body size and oxygen consumption, variation in maximum longevity was significantly explained by mitochondrial ROS production and cardiolipin content, but not by membrane resistance to oxidative attack. RBCs of longer-lived species produced less ROS and contained more cardiolipin than RBCs of shorter-lived species did. These results support the oxidative stress theory of ageing and shed light on mitochondrial cardiolipin as an important factor linking ROS production to longevity.

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NK cell-mediated antibody-dependent cellular cytotoxicity is enhanced by tamoxifen in HER2/neu non-amplified, but not HER2/neu-amplified, breast cancer cells

Abstract

Tumor-targeting antibodies have been successful in the treatment of various types of cancers. Antibodies engage the immune system with their Fc, stimulating immune cell effector function. In the clinic, FcγRIIIa polymorphisms with higher affinity for the Fc of antibodies were shown to improve response rates and overall survival. Efforts have been made to modify the Fc to enhance affinity to Fc receptors and thereby improve effector function. An alternative for improving immune effector function may be to increase the level of tumor antigen expression. In this study, tamoxifen was used to increase HER2/neu protein level to determine whether increased tumor antigen expression could enhance NK cell-mediated antibody-dependent cytotoxicity (ADCC). Tamoxifen was found to increase HER2/neu 1.5-fold to threefold in breast cancer cell lines that were HER2/neu non-amplified. Using flow cytometry to simultaneously evaluate NK cell degranulation and tumor cell death, the increase in HER2/neu enhanced NK cell-mediated ADCC. However, in cells that had HER2/neu gene amplification and estrogen receptor expression, tamoxifen elevated HER2/neu but failed to improve NK cell function. The quantity of HER2/neu on the tumor cell surface was approximately double that of the number of Fc receptors found on NK cells. This appears to reflect a ceiling at which increasing antigen expression fails to improve NK cell effector function. This has clinical implications as trying to increase antigen expression to enhance NK cell function may be useful for patients with antigen-low tumors, but not in those whose tumors have gene amplification or high levels of antigen expression.

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Re-irradiation for head and neck squamous cell carcinoma

Publication date: Available online 29 August 2016
Source:Journal of the Egyptian National Cancer Institute
Author(s): Rony Benson, Prashant Giridhar, Bhanu Prasad Venkatesulu, Supriya Mallick, Mohd Waseem Raza, Goura Kishor Rath
IntroductionLocal recurrences after curative treatment have a potential for cure with salvage surgery or with re-irradiation.MethodsWe reviewed the PubMed for articles published in English with key words squamous cell carcinoma, recurrent, re-irradiation, prognostic factors to find relevant articles describing prognostic factors, re-irradiation, and outcome for recurrent head and neck squamous cell carcinoma.ResultsVarious factors including age, performance status, time for recurrence, previous radiation dose volume and site of recurrence, previous use of chemotherapy are all prognostic factors in recurrent head and neck squamous cell carcinoma. Surgery is feasible in very select subgroup of patients and must be done when feasible. Re-irradiation with the aid of modern sophisticated technology is safe and confers durable and clinically meaningful survival benefit. Re-irradiation in head and neck recurrent squamous cell carcinoma may provide an expected median survival of 10–12months. Chemotherapy may be added along with radiation in the recurrent setting.ConclusionTreatment approaches may have to be personalized. Re surgery must be done in all patients in whom it is feasible. In patients in whom surgery is not feasible, re-irradiation must be evaluated as a therapeutic option especially in patients with limited volume recurrence.



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External beam radiation techniques for breast cancer in the new millennium: New challenging perspectives

Publication date: Available online 29 August 2016
Source:Journal of the Egyptian National Cancer Institute
Author(s): Dodul Mondal, Daya Nand Sharma
Radiation therapy in breast cancer has evolved dramatically over the past century. It has traveled a long path touching different milestones and taking unprecedented turns. At the end, a fine tune of clinical understanding, skill, technological advancement and translation of radiobiological understanding to clinical outcome has taken place. What all these have given is better survival with quality survivorship. It is thus prudent to understand breast irradiation in a new perspective suitable for the current millennium.



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Estrogen receptor expression and gene promoter methylation in non-small cell lung cancer - a short report

Abstract

Purpose

In the past, anomalous estrogen receptor (ER) regulation has been associated with various lung pathologies, but so far its involvement in lung cancer initiation and/or progression has remained unclear. Here, we aimed at assessing in vivo and in vitro ER expression and its possible epigenetic regulation in non-small cell lung cancer (NSCLC) samples and their corresponding normal tissues and cells.

Methods

ERα and ERβ gene expression levels were assessed using real time quantitative PCR (RT-qPCR), whereas ERα and ERβ gene promoter methylation levels were assessed using DNA bisulfite conversion followed by pyrosequencing. We included NSCLC (n = 87) and adjacent histologically normal lung tissue samples from lung cancer patients (n = 184), primary normal bronchial epithelial-derived cell cultures (n = 11), immortalized bronchial epithelial-derived cell lines (n = 3) and NSCLC derived cell lines (n = 9).

Results

Using RT-qPCR we found significantly lower ERα and ERβ expression levels in the NSCLC tissue samples compared to their normal adjacent tissue samples. These lower ER expression levels were confirmed in vitro using primary normal bronchial epithelial-derived cell cultures, immortalized bronchial epithelial-derived cell lines and NSCLC-derived cell lines. By using this latter panel of cells, we found that ER gene promoter hypermethylation was associated with decreased ER expression. In addition we found that in tumor and normal lung tissues, smoking was associated with decreased ER expression and that normal lung tissues with a low ERβ expression level exhibited increased smoking-related DNA adducts.

Conclusions

Taken together, our results indicate that decreased ER expression mediated by DNA methylation may play a role in NSCLC development.

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NK cell-mediated antibody-dependent cellular cytotoxicity is enhanced by tamoxifen in HER2/neu non-amplified, but not HER2/neu-amplified, breast cancer cells

Abstract

Tumor-targeting antibodies have been successful in the treatment of various types of cancers. Antibodies engage the immune system with their Fc, stimulating immune cell effector function. In the clinic, FcγRIIIa polymorphisms with higher affinity for the Fc of antibodies were shown to improve response rates and overall survival. Efforts have been made to modify the Fc to enhance affinity to Fc receptors and thereby improve effector function. An alternative for improving immune effector function may be to increase the level of tumor antigen expression. In this study, tamoxifen was used to increase HER2/neu protein level to determine whether increased tumor antigen expression could enhance NK cell-mediated antibody-dependent cytotoxicity (ADCC). Tamoxifen was found to increase HER2/neu 1.5-fold to threefold in breast cancer cell lines that were HER2/neu non-amplified. Using flow cytometry to simultaneously evaluate NK cell degranulation and tumor cell death, the increase in HER2/neu enhanced NK cell-mediated ADCC. However, in cells that had HER2/neu gene amplification and estrogen receptor expression, tamoxifen elevated HER2/neu but failed to improve NK cell function. The quantity of HER2/neu on the tumor cell surface was approximately double that of the number of Fc receptors found on NK cells. This appears to reflect a ceiling at which increasing antigen expression fails to improve NK cell effector function. This has clinical implications as trying to increase antigen expression to enhance NK cell function may be useful for patients with antigen-low tumors, but not in those whose tumors have gene amplification or high levels of antigen expression.

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Perceived barriers to treatment predict adherence to aromatase inhibitors among breast cancer survivors

BACKGROUND

Although poor adherence to hormonal therapies such as aromatase inhibitors (AIs) is widely documented, to the authors' knowledge less is known regarding whether health beliefs predict treatment nonadherence. The objective of the current study was to evaluate the relationship between health beliefs (perceived susceptibility to breast cancer, perceived benefits of AI treatment, and perceived barriers to AI treatment) and adherence to AIs.

METHODS

Postmenopausal women with early-stage, estrogen receptor-positive breast cancer who were currently receiving treatment with an AI completed the 3-factor Health Beliefs and Medication Adherence in Breast Cancer scale and questionnaires concerning their demographics and symptoms. Adherence data (treatment gaps and premature discontinuation) were abstracted from participants' medical charts. Logistic regression analyses were conducted to evaluate the relationship between health beliefs and adherence.

RESULTS

Among 437 participants, 93 (21.3%) were nonadherent. Those who perceived greater barriers to their AI treatment were more likely to demonstrate AI nonadherence behaviors by the end of their treatment period compared with those who reported fewer barriers to AI therapy (adjusted odds ratio, 1.71; 95% confidence interval, 1.03-2.86 [P = .04]). In contrast, perceived susceptibility to cancer recurrence and perceived benefits of AIs did not appear to predict AI adherence. Minority individuals were found to have lower perceived susceptibility to breast cancer recurrence and higher perceived barriers to AI treatment (P<.05 for both).

Conclusions

Greater perceived barriers appeared to predict nonadherence to AIs. Interventions addressing women's negative beliefs regarding the challenges of AI treatment are needed to help optimize adherence in survivors of breast cancer. Cancer 2016. © 2016 American Cancer Society.

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No 'cure within 12 years of diagnosis amongst breast cancer patients who are diagnosed via mammographic screening: women diagnosed in the West Midlands region of England 1989-2011

Despite dramatic improvements in survival over past decades, diagnosis with breast cancer leads to a small but persistent, long-term increased risk of death for all groups of women. This is also true for those whose cancer is detected asymptomatically via screening mammography.

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Sorafenib plus Hepatic Arterial Infusion Chemotherapy with Cisplatin vs. Sorafenib for Advanced Hepatocellular Carcinoma: Randomized Phase II Trial

In a randomized phase II study of sorafenib plus hepatic arterial infusion chemotherapy with cisplatin in comparison with sorafenib alone in patients with advanced hepatocellular carcinoma, it yielded favorable overall survival as compared to sorafenib. This is the first report of its effectiveness in relation to the overall survival in comparison with that of sorafenib in patients with advanced hepatocellular carcinoma.

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Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer

We previously hypothesized that peripheral antagonism of opioid-mediated effects may attenuate disease progression in cancer patients. Therefore, we explored pooled data from two randomized, placebo-controlled registration trials in patients with advanced disease and examined those with cancer to identify whether peripheral mu opioid receptor antagonist methylnaltrexone, which is used for treatment of opioid induced constipation, could influence patients' survival. In this retrospective combined post-hoc analysis we demonstrated that in patients with advanced terminal cancers and opioid induced constipation, treatment with methylnaltrexone and even more so response to treatment are associated with prolonged survival compared to placebo (76 days vs. 56 days, P=0.033) or no response (118 days vs. 55 days, P<0.001). Of interest, this was not the case for patients with advanced terminal illness other than cancer, where survival was not affected. Our data are consistent with the emerging preclinical literature demonstrating an effect of mu opiates on tumor progression, and several recent studies relating opiate dose to recurrence in the perioperative lung cancer setting and in advanced prostate cancer. Nevertheless, our findings should be interpreted as preliminary, hypothesis generating and insufficient to mandate a change in clinical practice, where pain control remains an important issue. Prospective clinical studies to confirm the role of methylnaltrexone in patients with advanced cancers are merited to confirm clinical relevance of our findings.

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The role of opioids in cancer progression: emerging experimental and clinical implications

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On the Generalizability of Prostate Cancer Studies: Why Race Matters

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Reply to the letter to the editor 'Utilisation of the ESMO-MCBS in practice of HTA by Wild et al

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Pictilisib plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study

The PEGGY study failed to meet its primary endpoint, with no improvement in progression-free survival in patients who received pictilisib plus paclitaxel versus placebo plus paclitaxel in either the intention-to-treat population or in patients with PIK3CA-mutated tumours.

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Phase III trial comparing 3 to 6 months of adjuvant FOLFOX4/XELOX in stage II-III colon cancer: safety and compliance in the TOSCA trial

TOSCA trial investigates if 3 months of adjuvant FOLFOX4/XELOX is equally efficacious to 6 months in colon cancer. Adherence to planned program was good in both arms, with more than 5 months of therapy on average in arm 6m. Grade 3+ toxicities were higher in arm 6m, especially neuropathy. High compliance to therapy will allow correct assessment of differences between the two treatment durations.

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Subgroup analysis in RAISE: A randomized, double-blind phase 3 study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression

The RAISE phase 3 trial demonstrated that ramucirumab+FOLFIRI improved survival compared to placebo+FOLFIRI for second-line metastatic colorectal carcinoma patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Analyses reported here found similar efficacy and safety in patients regardless of KRAS mutational status, time to first-line progression, and age.

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NK cell-mediated antibody-dependent cellular cytotoxicity is enhanced by tamoxifen in HER2/neu non-amplified, but not HER2/neu-amplified, breast cancer cells

Abstract

Tumor-targeting antibodies have been successful in the treatment of various types of cancers. Antibodies engage the immune system with their Fc, stimulating immune cell effector function. In the clinic, FcγRIIIa polymorphisms with higher affinity for the Fc of antibodies were shown to improve response rates and overall survival. Efforts have been made to modify the Fc to enhance affinity to Fc receptors and thereby improve effector function. An alternative for improving immune effector function may be to increase the level of tumor antigen expression. In this study, tamoxifen was used to increase HER2/neu protein level to determine whether increased tumor antigen expression could enhance NK cell-mediated antibody-dependent cytotoxicity (ADCC). Tamoxifen was found to increase HER2/neu 1.5-fold to threefold in breast cancer cell lines that were HER2/neu non-amplified. Using flow cytometry to simultaneously evaluate NK cell degranulation and tumor cell death, the increase in HER2/neu enhanced NK cell-mediated ADCC. However, in cells that had HER2/neu gene amplification and estrogen receptor expression, tamoxifen elevated HER2/neu but failed to improve NK cell function. The quantity of HER2/neu on the tumor cell surface was approximately double that of the number of Fc receptors found on NK cells. This appears to reflect a ceiling at which increasing antigen expression fails to improve NK cell effector function. This has clinical implications as trying to increase antigen expression to enhance NK cell function may be useful for patients with antigen-low tumors, but not in those whose tumors have gene amplification or high levels of antigen expression.

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Correlating mammographic and pathologic findings in clinical decision support using natural language processing and data mining methods

BACKGROUND

A key challenge to mining electronic health records for mammography research is the preponderance of unstructured narrative text, which strikingly limits usable output. The imaging characteristics of breast cancer subtypes have been described previously, but without standardization of parameters for data mining.

METHODS

The authors searched the enterprise-wide data warehouse at the Houston Methodist Hospital, the Methodist Environment for Translational Enhancement and Outcomes Research (METEOR), for patients with Breast Imaging Reporting and Data System (BI-RADS) category 5 mammogram readings performed between January 2006 and May 2015 and an available pathology report. The authors developed natural language processing (NLP) software algorithms to automatically extract mammographic and pathologic findings from free text mammogram and pathology reports. The correlation between mammographic imaging features and breast cancer subtype was analyzed using one-way analysis of variance and the Fisher exact test.

RESULTS

The NLP algorithm was able to obtain key characteristics for 543 patients who met the inclusion criteria. Patients with estrogen receptor-positive tumors were more likely to have spiculated margins (P = .0008), and those with tumors that overexpressed human epidermal growth factor receptor 2 (HER2) were more likely to have heterogeneous and pleomorphic calcifications (P = .0078 and P = .0002, respectively).

CONCLUSIONS

Mammographic imaging characteristics, obtained from an automated text search and the extraction of mammogram reports using NLP techniques, correlated with pathologic breast cancer subtype. The results of the current study validate previously reported trends assessed by manual data collection. Furthermore, NLP provides an automated means with which to scale up data extraction and analysis for clinical decision support. Cancer 2016. © 2016 American Cancer Society.

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Impact of facility volume on outcomes in patients with squamous cell carcinoma of the anal canal: Analysis of the National Cancer Data Base

BACKGROUND

Given the rarity of anal cancer and the technical aspects involved in radiation (RT) planning, the authors conducted a population-based analysis evaluating the impact of radiation oncology facility volume on overall survival (OS) in patients with squamous cell carcinoma (SCC) of the anal canal.

METHODS

The National Cancer Data Base (NCDB) was queried for patients with SCC of the anal canal who underwent RT. All patients were coded as having received their entire course of RT at the NCDB reporting facility. Facility volume was categorized into tertiles (low, intermediate, and high) and was based on the number of times a facility's unique identification code appeared.

RESULTS

In total, 13,550 patients were identified. Patients who received treatment at higher volume radiation oncology facilities had longer OS based on multivariate analysis (MVA) (hazard ratio, 0.81; 95% confidence interval [CI], 0.73-0.90; P < .001) and propensity score matching analysis (hazard ratio, 0.79; 95% CI, 0.69-0.91; P < .001). For patients who received treatment at low-volume, intermediate-volume, and high-volume centers, the 5-year OS rate was 70%, 72.2%, and 75.4%, respectively (P < .001). Compared with low/intermediate-volume radiation oncology centers, high-volume centers were more likely to treat patients with concurrent chemotherapy (odds ratio, 1.27; 95% CI, 1.07-1.51; P = .006) and less likely to have treatment delays leading to an RT duration of >45 days (odds ratio, 0.74; 95% CI, 0.69-0.80; P < .001).

CONCLUSIONS

Treatment at higher volume radiation oncology centers appears to be associated with improved OS in patients with SCC of the anal canal. These results likely reflect the relation between physician experience and delivery of high-quality RT, which perhaps is best evident in rare tumors such as anal SCC. Cancer 2016. © 2016 American Cancer Society.

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Issue Information - TOC

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Issue Information - Ed Board

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Cancers, Vol. 8, Pages 80: Wnt Signaling in Cell Motility and Invasion: Drawing Parallels between Development and Cancer

The importance of canonical and non-canonical Wnt signal transduction cascades in embryonic development and tissue homeostasis is well recognized. The aberrant activation of these pathways in the adult leads to abnormal cellular behaviors, and tumor progression is frequently a consequence. Here we discuss recent findings and analogies between Wnt signaling in developmental processes and tumor progression, with a particular focus on cell motility and matrix invasion and highlight the roles of the ARF (ADP-Ribosylation Factor) and Rho-family small GTP-binding proteins. Wnt-regulated signal transduction from cell surface receptors, signaling endosomes and/or extracellular vesicles has the potential to profoundly influence cell movement, matrix degradation and paracrine signaling in both development and disease.

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17β-hydroxysteroid dehydrogenase type Gene 1 937 A > G Polymorphism as a Risk Factor for Cervical Cancer Progression in the Polish Population

Abstract

The role of 17β-estradiol (E2) in the development of cervical tumor (CT) has been demonstrated. 17β Hydroxysteroid dehydrogenase type 1 (HSD17B1) converts estrone (E1) into E2. We aimed to study the distribution of the HSD17B1937 A > G (rs605059) single nucleotide polymorphism (SNP) in women (n = 383) with CT and controls (n = 401) from the Polish population. The p-trend value evaluated for HSD17B1 rs605059 was 0.0233 for all patients. The A/A vs G/G genotype significantly contributed to all patients with CT, and the Odds Ratio (OR) was 1.570 (95 % CI = 1.053–2.343; p = 0.0266). Stratification of the patients based on tumor stage and histological grade indicated the contribution of HSD17B1937 A > G to stages III and IV. The p-value was 0.0010. The OR for the A/A vs G/G genotype was 2.992 (95 % CI = 1.627–5.502, p = 0.0003), the OR for the A/G vs G/G genotype was 2.545 (95 % CI = 1.410–4.593, p = 0.0015) and the OR for the A/A and A/G vs G/G genotype was 2.724 (95 % CI = 1.546–4.799, p = 0.0004). Moreover, we observed a contribution of the rs605059 SNP to histological grade G3 status. The p-value was 0.0042. The OR for the A/A vs G/G genotype was 5.632 (95 % CI = 1.644–19.290, p = 0.0026), the OR for the A/G vs G/G genotype was 4.213 (95 % CI = 1.244–14.265, p = 0.0113) and the OR for the A/A and A/G vs G/G genotype was 4.780 (95 % CI = 1.456–15.687, p = 0.0033). Our study indicated that the HSD17B1937 A > G transition is a risk factor for CT, especially for stages III and IV and histological grade G3.

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Clinicopathological Features and Treatment Analysis of Rare Aggressive Angiomyxoma of the Female Pelvis and Perineum – a Retrospective Study

Abstract

The study was to evaluate the clinicopathological features of aggressive angiomyxoma (AAM) of the female pelvis and perineum and its treatments. This was a retrospective study of female patients with AAM admitted to our hospital. Clinical and pathological data were analyzed, as well as the postsurgical follow-up. Median age at initial presentation was 41 years. Thirteen patients had lesions involving adjacent organs. Eighteen patients underwent complete tumor resection, while one patient underwent partial tumor resection. The tumors were soft in texture, pink in color, and had mucus on the surface. A microscopic examination revealed that the tumors were non-encapsulated, with spindle cells and stellate cells of almost identical size loosely distributed in the myxoid stroma, and vessels of different sizes and wall thicknesses. Immunohistochemistry indicated that AAMs were strongly positive for CD34 and smooth muscle actin, moderately positive for desmin, estrogen receptors and progesterone receptor, and mostly negative for S-100. After a median follow-up of 24 months, the recurrence rate was 33.3 %. Four recurrences were in patients with positive initial margins. AAM is a slow growing, locally invasive, benign tumor. Complete resection could lead to lower recurrence rate compared with incomplete resection. Follow-up is necessary for recurrent cases with repeated surgeries. The overall prognosis could be favorable.

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Frameshift Mutations in the Mononucleotide Repeats of TAF1 and TAF1L Genes in Gastric and Colorectal Cancers with Regional Heterogeneity

Abstract

Initiation of transcription by RNA polymerase II requires TATA-box-binding protein (TBP)-associated factors (TAFs). TAF1 is a major scaffold by which TBP and TAFs interact in the basal transcription factor. TAF1L is a TAF1 homologue with 95 % amino acid identity with TAF1. TAF1 is involved in apoptosis induction and cell cycle regulation, but roles of TAF1 and TAF1L in tumorigenesis remain unknown. The aim of this study was to explore whether TAF1 and TAF1L genes were mutated in gastric (GC) and colorectal cancers (CRC). In a public database, we found that TAF1 and TAF1L genes had mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with microsatellite instability (MSI). We analyzed the mutations in 79 GC and 124 CRC by single-strand conformation polymorphism analysis and DNA sequencing. In the present study, we found TAF1 frameshift mutations (3.8 % of CRC with MSI-H) and TAF1L frameshift mutations (2.9 % of GC and 3.8 % of CRC with MSI-H). These mutations were not found in stable MSI/low MSI (MSS/MSI-L) (0/90). In addition, we analyzed intratumoral heterogeneity (ITH) of TAF1 and TAF1L frameshift mutations in 16 CRC and found that two and one CRC harbored regional ITH of TAF1 and TAF1L frameshift mutations, respectively. Our data indicate that TAF1 and TAF1L genes harbored not only somatic mutations but also mutational ITH, which together might play a role in tumorigenesis of GC and CRC with MSI-H. Our results also suggest that ultra-regional mutation analysis is required for a comprehensive evaluation of mutation status in these tumors.

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Frameshift Mutation of ASPM Gene in Colorectal Cancers with Regional Heterogeneity

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Analysis of DNA Repair Genes Polymorphisms in Breast Cancer

Abstract

Genetic polymorphisms in the DNA repair genes may be associated with increased cancer risk. The purpose of this study was to evaluate the association of the DNA repair genes polymorphisms with the risk of breast cancer development. The study included 200 breast cancer patients and 200 healthy controls. The following polymorphisms were studied: C/G (Ser326Cys, rs1052133) of the hOGG1, A/C (IVS5 + 33, rs3212961) of the ERCC1, A/C (Lys939Gln, rs2228001) of the XPC, C/T (Thr241Met, rs861539) of the XRCC3, G/T (Leu787Leu, rs1800392) of the WRN and G/T (Ser307Ser, rs1056503) of the XRCC4 gene. Presented study showed statistically significant increase in the breast cancer development risk of the G/G hOGG1 genotype (OR 8.13; 95 % CI, 4.37–15.14; p < 0.001) and for the G hOGG1 allele (OR 5.11; 95 % CI, 3.69–7.06; p < 0.001), as well as for the C/C ERCC1 genotype (OR 10.61; 95 % CI, 5.72–19.69; p < 0.001) and the C ERCC1 allele (OR 4.66; 95 % CI, 3.43–6.34; p < 0.001) in patients with breast cancer in comparison with healthy control group. We also observed positive association of the C/C XPC genotype (OR 3.80; 95 % CI, 2.27–6.38; p < 0.001) as well as the C XPC allele occurrence with an increased breast cancer development risk (OR 2.65; 95 % CI, 1.98–3.55; p < 0.001). Furthermore, we found an association of the G/T WRN gene polymorphism with increased risk of carcinoma. The hOGG1, ERCC1, XPC and WRN genes polymorphisms may be related to development of breast cancer.

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Transient spontaneous remission in congenital MLL-AF10 rearranged acute myeloid leukemia presenting with cardiorespiratory failure and meconium ileus

Abstract

Background

Neonatal leukemia is a rare disease with an estimated prevalence of about one to five in a million neonates. The majority being acute myeloid leukemia (AML), neonatal leukemia can present with a variety of symptoms including hyperleucocytosis, cytopenia, hepatosplenomegaly, and skin infiltrates. Chromosomal rearrangements including mixed lineage leukemia (MLL) translocations are common in neonatal AML.

Case presentation

A female neonate born at 34 weeks gestation presented with cardiorespiratory failure, hepatosplenomegaly, pancytopenia, and coagulopathy. She required intensive care treatment including mechanical ventilation, high-dose catecholamine therapy, and multiple transfusions. Small intestinal biopsy obtained during laparotomy for meconium ileus revealed an infiltrate by an undifferentiated monoblastic, MLL-rearranged leukemia. No other manifestations of leukemia could be detected. After spontaneous clinical remission, lasting 5 months without any specific treatment, the patient presented with leukemia cutis and full-blown monoblastic leukemia. MLL-AF10-rearranged AML could be re-diagnosed and successfully treated with chemotherapy and hematopoietic stem cell transplantation.

Conclusions

Our patient exhibited a unique manifestation of neonatal MLL-AF10 rearranged AML with cardiorespiratory failure and intestinal infiltration. It highlights the importance of leukemia in the differential diagnosis of neonatal distress, congenital hematological abnormalities, and skin lesions.

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Oral health and human papillomavirus-associated head and neck squamous cell carcinoma

BACKGROUND

Indicators of poor oral health, including smoking, have been associated with increased risk of head and neck squamous cell carcinoma, especially oropharyngeal squamous cell carcinoma (OPSCC), yet few studies have examined whether this association is modified by human papillomavirus (HPV) status.

METHODS

Data from interviews and tumor HPV status from a large population-based case-control study, the Carolina Head and Neck Cancer Study (CHANCE), were used to estimate the association between oral health indicators and smoking among 102 HPV-positive patients and 145 HPV-negative patients with OPSCC and 1396 controls. HPV status was determined by p16INK4a (p16) immunohistochemistry. Unconditional, multinomial logistic regression was used to estimate odds ratios (ORs) for all oral health indictors adjusting for important covariates.

RESULTS

Routine dental examinations were associated with a decreased risk of both HPV-negative OPSCC (OR, 0.52; 95% confidence interval [CI], 0.35-0.76) and HPV-positive OPSCC (OR, 0.55; 95% CI, 0.36-.86). Tooth mobility (a proxy for periodontal disease) increased the risk of HPV-negative disease (OR, 1.70; 95% CI, 1.18-2.43) slightly more than the risk for HPV-positive disease (OR, 1.45; 95% CI, 0.95-2.20). Ten or more pack-years of cigarette smoking were strongly associated with an increased risk of HPV-negative OPSCC (OR, 4.26; 95% CI, 2.85-6.37) and were associated less with an increased risk of HPV-positive OPSCC (OR, 1.62; 95% CI, 1.10-2.38).

CONCLUSIONS

Although HPV-positive and HPV-negative HNSCC differ significantly with respect to etiology and tumorigenesis, the current findings suggest a similar pattern of association between poor oral health, frequency of dental examinations, and both HPV-positive and HPV-negative OPSCC. Future research is required to elucidate interactions between poor oral health, tobacco use, and HPV in the development of OPSCC. Cancer 2016. © 2016 American Cancer Society.

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Impact of country of birth on age at the time of diagnosis of hepatocellular carcinoma in the United States

BACKGROUND

There is global variation in the onset of hepatocellular carcinoma (HCC). The objective of the current study was to investigate the impact of country of birth on age at the time of HCC diagnosis in the United States.

METHODS

Incident HCC cases diagnosed between 2000 and 2012 in the Surveillance, Epidemiology, and End Results program 18 registry were included. Factors associated with very early onset (age at diagnosis < 40 years) and early onset (age at diagnosis < 50 years) were identified by logistic regression.

RESULTS

A total of 59,907 patients were included. The median age at the time of diagnosis of HCC was 62 years and 76% of the patients were male. Of the 75% of patients for whom information regarding birth country was available, 29% were foreign born. In multivariate logistic regression, birth in West Africa (adjusted odds ratio [AOR], 16.3; 95% confidence interval [95% CI], 9.2-27.9 [P<.01]), Central/South/other Africa (AOR, 11.0; 95% CI, 4.5-23.7 [P<.01]), Oceania (AOR, 4.9; 95% CI, 2.9-8.0 [P<.01]), and East Africa (AOR, 3.5; 95% CI, 1.5-6.8 [P<.01]) was found to have the strongest association with very early-onset HCC after adjusting for sex and race/ethnicity. Birth in West Africa, Central/South/other Africa, Oceania, or East Africa also was found to be strongly associated with early-onset HCC.

CONCLUSIONS

Birth country was found to be independently associated with age at the time of HCC diagnosis in the United States. Birth in Africa (except for North Africa) and Oceania was strongly associated with very early-onset HCC. These findings have implications for the design of comprehensive HCC surveillance programs in the United States. Cancer 2016. © 2016 American Cancer Society.

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A prospective study of cerebral, frontal lobe, and temporal lobe volumes and neuropsychological performance in children with primary brain tumors treated with cranial radiation

BACKGROUND

Cranial radiation therapy (RT) is an important component in the treatment of pediatric brain tumors. However, it can result in long-term effects on the developing brain. This prospective study assessed the effects of cranial RT on cerebral, frontal lobe, and temporal lobe volumes and their correlation with higher cognitive functioning.

METHODS

Ten pediatric patients with primary brain tumors treated with cranial RT and 14 age- and sex-matched healthy children serving as controls were evaluated. Quantitative magnetic resonance imaging and neuropsychological assessments (language, memory, auditory and visual processing, and vocabulary) were performed at the baseline and 6, 15, and 27 months after RT. The effects of age, the time since RT, and the cerebral RT dose on brain volumes and neuropsychological performance were analyzed with linear mixed effects model analyses.

RESULTS

Cerebral volume increased significantly with age in both groups (P = .01); this increase in volume was more pronounced in younger children. Vocabulary performance was found to be significantly associated with a greater cerebral volume (P = .05) and a lower RT dose (P = .003). No relation was observed between the RT dose and the cerebral volume. There was no difference in the corresponding neuropsychological tests between the 2 groups.

CONCLUSIONS

This prospective study found significant relations among the RT dose, cerebral volumes, and rate of vocabulary development among children receiving RT. The results of this study provide further support for clinical trials aimed at reducing cranial RT doses in the pediatric population. Cancer 2016. © 2016 American Cancer Society.

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MicroRNA-127 is aberrantly downregulated and acted as a functional tumor suppressor in human pancreatic cancer

Abstract

Pancreatic carcinoma is one of the most malignant human cancers. In this study, we intended to explore the molecular functional of microRNA-127 (miR-127) in regulating pancreatic cancer development both in vitro and in vivo. Quantitative real-time PCR (qRT-PCR) was performed to evaluate endogenous miR-127 expression in in vitro pancreatic cancer cell lines and in vivo clinical samples of pancreatic carcinoma. Lentiviral technology was applied to overexpress miR-127 in capan-1 and PANC-1 cells. Pancreatic cancer proliferation, cell-cycle progression, and invasion were assessed in vitro, and capan-1-derived tumorigenicity was evaluated in vivo. Dual-luciferase reporter assay and qRT-PCR were performed to assess the downstream target gene of miR-127 in pancreatic cancer, human Bcl-2-associated athanogene 5 (BAG5). BAG5 was subsequently upregulated in miR-127-overexpressed capan-1 and PANC-1 cells to evaluate its effect on pancreatic cancer progression. MiR-127 was preferentially downregulated in both pancreatic carcinoma cell lines and human pancreatic tumors. In lentivirus-infected capan-1 and PANC-1 cells, miR-127 overexpression significantly inhibited cancer progression, cell-cycle transition and invasion in vitro, as well as tumorigenicity in vivo. Human BAG5 was confirmed to be the downstream target of miR-127 in pancreatic cancer. Forced overexpression of BAG5 in capan-1 and PANC-1 cells reversed the tumor-suppressing effect of miR-127 on cancer development. MiR-127 is downregulated and acting as a tumor suppressor in pancreatic carcinoma. The functional regulation of miR-127 in pancreatic carcinoma is very likely through the inverse correlation of its downstream target gene of BAG5.

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Targeted deactivation of cancer-associated fibroblasts by β-catenin ablation suppresses melanoma growth

Abstract

Cancer-associated fibroblasts (CAFs) are the crucial components of the dynamic tumor microenvironment, which not only supports the growth and metastasis of melanoma but also contributes to drug resistance in melanoma treatment. We recently discovered that loss of β-catenin signaling deactivated stromal fibroblasts and reduced the production of paracrine factors and extracellular matrix proteins. Based on this finding, we aimed to determine whether melanoma growth could be suppressed by targeted deactivation of CAFs via β-catenin ablation using a combination of in vitro and in vivo approaches. Using an in vitro three-dimensional (3D) tumor co-culture model, we showed that β-catenin-deficient fibroblasts lost the ability to respond to melanoma cell stimulation and to support the growth of B16F10 melanoma cells. To determine the in vivo effects of CAF deactivation on melanoma growth, we designed a novel genetic approach to ablate β-catenin expression in melanoma-associated fibroblasts only after melanoma tumor was formed. As expected, our observation showed that development of B16F10 melanoma was significantly delayed when β-catenin expression was ablated in CAFs. We determined that inhibition of tumor growth was due to decreased melanoma cell proliferation and increased cell death. Further analysis revealed that CAF deactivation caused the downregulation of the MAPK/ERK signaling cascade and S and G2/M phase cell cycle arrest in B16F10 melanoma cells. Overall, our data emphasize the significance of targeting CAFs as a potential novel therapeutic approach to improve melanoma treatment by creating a tumor-suppressive microenvironment through tumor-stroma interactions.

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From the Desk of the Editor

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