Role of ROS-induced p53 in CLL.

Chronic lymphocytic leukemia (CLL) cells multiply and become more resistant to immunochemotherapy in 'proliferation centers' within tissues, whereas apoptosis occurs in the periphery. Various models recapitulate these microenvironments in vitro, such as stimulation with CD154 and IL-4. Using this system, we observed a 30-40 fold induction of wild-type p53 protein in 50 distinct human CLL specimens tested, without the induction of either cell cycle arrest or apoptosis. In contrast, the mRNA levels for p53 did not increase, indicating that its elevation occurred posttranscriptionally. Mechanistic investigations revealed that under the conditions studied p53 was phosphorylated on residues associated with p53 activation and increased half-life. However, p53 protein induced in this manner could transcriptionally activate only a subset of target genes. The addition of a DNA damaging agent further upregulated p53 protein levels which led to apoptosis. p53 induction relied on the increase in intracellular reactive oxygen species (ROS) observed after CD154 and IL-4 stimulation. We propose that chronic oxidative stress is a characteristic of the microenvironment in B cell 'proliferation centers' in CLL which are capable of elevating the basal expression of p53, but to levels below the threshold needed to induce arrest or apoptosis. Our findings suggest that reactivation of the full transcriptional activities of p53 in proliferating CLL cells may offer a possible therapeutic strategy.

from Cancer via ola Kala on Inoreader http://ift.tt/2cjuyMI
via IFTTT

Role of CD166 in multiple myeloma progression

Multiple myeloma (MM) is incurable once osteocytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166- cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells. CD166 deficiency in MM cell lines or CD138+ BM cells from MM patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Further, CD166 deficiency in MM cells also reduced formation of osteolytic disease in vivo after intra-tibial engraftment. Mechanistic investigation revealed that CD166 expression in MM cells inhibited osteoblastogenesis of BM-derived osteoblast progenitors by suppressing RUNX2 gene expression. Conversely, CD166 expression in MM cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in MM cell homing to the BM and MM progression, rationalizing its further study as a candidate therapeutic target for MM treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/2c6SG1v
via IFTTT

NRBP2 promotes HCC cell chemosensitivity

Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy. Research data supported that cancer stem cells (CSCs) may be responsible for the chemoresistance, and strategies that suppress CSCs stemness could also inhibit the drug resistance. In this study, we found that NRBP2 expression was downregulated in the CD133+ HCC CSCs. Most adjacent non-cancerous liver tissue analyzed expressed higher level of NRBP2 compared with cancerous tissue in HCC patients, and high NRBP2 expression indicated a better prognosis. Realtime PCR results showed that NRBP2 negatively correlated with stemness-related genes, including Oct3/4, Nanog, Notch1, Ep300 and CD133 mRNA expression. High NRBP2 expression in HCC cells downregulated CK19 protein expression, inhibited tumorsphere formation and tumorigenesis ability, indicates that high NRBP2 expression restrains the HCC cell stemness. Overexpression of NRBP2 reduced the IC50 of sorafenib in HCC cells, and NRBP2 expression was negatively correlated with HCC cell resistance to the chemotherapy agents, including cisplatin and the Akt signaling inhibitor perifosine. Co-immunoprecipitation results showed that NRBP2 could bind with annexin A2 (ANXA2) and inhibit ANXA2 expression. Co-expression of ANXA2 restored the chemoresistant ability in NRBP2-overexpressing HCC cells. Further analysis showed that that NRBP2 downregulated Akt and its downstream signaling target Bad phosphorylation level. ANXA2 co-expression partially restored the Akt phosphorylation. Analysis of the expression of Bcl2 family proteins showed that NRBP2 may increase HCC cell chemosensitivity by regulating expression of survival proteins involved in the Akt and Bcl2 pathway. These results suggest that NRBP2 plays an important role in the tumor progression and chemotherapeutic resistance of HCC.

from Cancer via ola Kala on Inoreader http://ift.tt/2cjtYyj
via IFTTT

Epigenetic Alterations in Unfavorable Neuroblastomas

The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor- and cell line–derived global histone modification analyses and epigenetic drug treatment in vitro. We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN. Transcriptome integration and histone modification–based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk–associated transcriptional deregulation. Furthermore, in high-risk neuroblastomas, we obtained evidence for cooperation between PRC2 activity and DNA methylation in blocking tumor-suppressive differentiation programs. Notably, these programs could be re-activated by combination treatments, which targeted both PRC2 and DNA methylation. Overall, our results illuminate how epigenetic deregulation contributes to neuroblastoma pathogenesis, with novel implications for its diagnosis and therapy. Cancer Res; 76(18); 1–15. ©2016 AACR.

from Cancer via ola Kala on Inoreader http://ift.tt/2c6Sr6F
via IFTTT

Antimetastatic activity of novel ruthenium (III) pyridine complexes

Abstract

Ruthenium-based complexes have emerged as promising anticancer, especially antimetastatic agents. Among them, NAMI-A (trans-[Ru(III)Cl₄ (DMSO)(Im)][ImH], Im = imidazole, DMSO = dimethyl sulfoxide) was well studied. In this study, we studied the antimetastatic activities of two novel NAMI-A derivatives containing pyridine, G26b and G94a, using cultured cells and tumor-bearing mice. Same to NAMI-A, these two complexes displayed little direct cytotoxicity to the cancer cells in vitro and in vivo, but they, especially G26b, significantly reduced the occurrence and development of lung metastases in mice bearing the 4T1 mammary carcinoma. In vitro, these two complexes displayed significant suppressive effect on invasion and migration of cells and tube formation of human umbilical vein endothelial cell, to the same extent of NAMI-A. The transcription of important molecules involved in metastasis, matrix metalloproteinase 2 and 9 (MMP-2 and -9), and vascular endothelial growth factor, was suppressed by the two complexes, as well as NAMI-A. Plasma atomic emission spectrometer showed G26b had a longer Ru-elimination time in lung, which may be a reason for better antimetastatic effect of G26b than NAMI-A. Our results have demonstrated that G26b is a more effective antimetastatic agent than NAMI-A.

The ruthenium (III)-pyridine complexes, G26b and G94a, which is derived from NAMI-A, could strongly reduce the occurrence and development of lung metastases in mice when kept a slower Ru elimination, which prolonged contact with the metastatic cells in the lungs. The ruthenium (III)-pyridine complexes had coped better than well-studied NAMI-A.

from Cancer via ola Kala on Inoreader http://ift.tt/2c8Ljpo
via IFTTT

A study on the value of computer-assisted assessment for SPECT/CT-scans in sentinel lymph node diagnostics of penile cancer as well as clinical reliability and morbidity of this procedure

Abstract

Background

Because of the increasing importance of computer-assisted post processing of image data in modern medical diagnostic we studied the value of an algorithm for assessment of single photon emission computed tomography/computed tomography (SPECT/CT)-data, which has been used for the first time for lymph node staging in penile cancer with non-palpable inguinal lymph nodes. In the guidelines of the relevant international expert societies, sentinel lymph node-biopsy (SLNB) is recommended as a diagnostic method of choice. The aim of this study is to evaluate the value of the afore-mentioned algorithm and in the clinical context the reliability and the associated morbidity of this procedure.

Methods

Between 2008 and 2015, 25 patients with invasive penile cancer and inconspicuous inguinal lymph node status underwent SLNB after application of the radiotracer Tc-99m labelled nanocolloid. We recorded in a prospective approach the reliability and the complication rate of the procedure. In addition, we evaluated the results of an algorithm for SPECT/CT-data assessment of these patients.

Results

SLNB was carried out in 44 groins of 25 patients. In three patients, inguinal lymph node metastases were detected via SLNB. In one patient, bilateral lymph node recurrence of the groins occurred after negative SLNB. There was a false-negative rate of 4 % in relation to the number of patients (1/25), resp. 4.5 % in relation to the number of groins (2/44). Morbidity was 4 % in relation to the number of patients (1/25), resp. 2.3 % in relation to the number of groins (1/44). The results of computer-assisted assessment of SPECT/CT data for sentinel lymph node (SLN)-diagnostics demonstrated high sensitivity of 88.8 % and specificity of 86.7 %.

Conclusions

SLNB is a very reliable method, associated with low morbidity. Computer-assisted assessment of SPECT/CT data of the SLN-diagnostics shows high sensitivity and specificity. While it cannot replace the assessment by medical experts, it can still provide substantial supplement and assistance.

from Cancer via ola Kala on Inoreader http://ift.tt/2cHvsTK
via IFTTT

Promising novel therapeutic approaches in the management of gastrointestinal stromal tumors

Future Oncology Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2cDg86p
via IFTTT