Meiosis-like Functions in Oncogenesis: A New View of Cancer

Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 1–5. ©2017 AACR.

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miR-6883 family miRNAs target CDK4/6 to induce G1 phase cell cycle arrest in colon cancer cells

CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and TCGA dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer (CRC). The 3′UTR of CDK4/6 mRNAs are targeted by a family of miRNAs which includes miR-6883-5p, miR-149*, miR-6785-5p and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human CRC cells. RNA-seq analysis revealed an inverse relationship between the expression of CDK4/6 and miR-149* and intronic miRNA-6883-5p encoding the clock gene PER1 in CRC patient samples. Restoring expression of miR-6883-5p and miR-149* blocked cell growth leading to G0/G1 phase cell cycle arrest and apoptosis in CRC cells. CDK4/6 targeting by miR-6883-5p and miR-149* could only partially explain the observed anti-proliferative effects. Notably, both miRNAs synergized with the frontline CRC chemotherapy drug irinotecan. Further, they re-sensitized mutant p53-expressing cell lines resistant to 5-fluorouracil. Taken together, our results established the foundations of a candidate miRNA-based theranostic strategy to improve CRC management.

from Cancer via ola Kala on Inoreader http://ift.tt/2iwG8ax
via IFTTT

Meiosis-like Functions in Oncogenesis: A New View of Cancer

Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 1–5. ©2017 AACR.

http://ift.tt/2z2vaAQ

miR-6883 family miRNAs target CDK4/6 to induce G1 phase cell cycle arrest in colon cancer cells

CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and TCGA dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer (CRC). The 3′UTR of CDK4/6 mRNAs are targeted by a family of miRNAs which includes miR-6883-5p, miR-149*, miR-6785-5p and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human CRC cells. RNA-seq analysis revealed an inverse relationship between the expression of CDK4/6 and miR-149* and intronic miRNA-6883-5p encoding the clock gene PER1 in CRC patient samples. Restoring expression of miR-6883-5p and miR-149* blocked cell growth leading to G0/G1 phase cell cycle arrest and apoptosis in CRC cells. CDK4/6 targeting by miR-6883-5p and miR-149* could only partially explain the observed anti-proliferative effects. Notably, both miRNAs synergized with the frontline CRC chemotherapy drug irinotecan. Further, they re-sensitized mutant p53-expressing cell lines resistant to 5-fluorouracil. Taken together, our results established the foundations of a candidate miRNA-based theranostic strategy to improve CRC management.

http://ift.tt/2iwG8ax

Thrombosis in adult patients with acute leukemia

Purpose of review: Recent studies indicate that the risk of thrombosis in hematologic patients may be similar or even higher than that found in patients with solid tumors. However, available information about pathogenesis and incidence of thrombosis in acute leukemia is limited. This review focuses on mechanisms underlying thrombosis in acute leukemia and discusses recent literature data. Recent findings: In the last few years, proofs have been provided that leukemic cells release free prothrombotic products, such as micro-vesicles, tissue factors, circulating free DNA and RNA. Furthermore, leukemic blasts can activate the procoagulant population of platelets, which initiate and amplify coagulation, causing thrombosis. In addition to factors produced by acute leukemia itself, others concur to trigger thrombosis. Some drugs, infections and insertion of central venous catheter have been described to increase risk of thrombosis in patients with acute leukemia. Summary: Thrombosis represents a serious complication in patients affected by myeloid and lymphoid acute leukemia. A proper knowledge of its pathophysiology and of the predisposing risk factors may allow to implement strategies of prevention. Improving prevention of thrombosis appears a major goal in patients whose frequent conditions of thrombocytopenia impede an adequate delivery of anticoagulant therapy.

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Stop and go: hematopoietic cell transplantation in the era of chimeric antigen receptor T cells and checkpoint inhibitors

Purpose of review: For several decades, hematopoietic cell transplantation (HCT) has been considered the standard curative therapy for many patients with hematological malignancies. In addition to the cytotoxic effects of the chemotherapy and radiation used in the conditioning regimen, the benefits of HCT are derived from a reset of the immune system and harnessing the ability of donor T cells to eliminate malignant cells. With the dawn of the era of immunotherapies in the form of checkpoint inhibitors and chimeric antigen receptor (CAR) T cells, the role of HCT has evolved. Recent findings: Immunotherapy with checkpoint inhibitors is increasingly being used for relapsed Hodgkin and non-Hodgkin lymphoma after autologous HCT. Checkpoint inhibitors are also being tested after allogeneic HCT with observable benefits in treating hematological malignancies, but with a potential risk of increased graft versus host disease and transplant-related mortality. Immunotherapy with Cluster of differentiation 19 CAR T cells are powerful options with aggressive B-cell malignancies both for therapy and as induction leading to allogeneic HCT. Summary: Although immunotherapies with checkpoint inhibition and CAR T cells are increasingly being used to treat hematological malignancies, HCT remains a standard of care for most of the diseases with the best chance of cure. Combination of these therapies with HCT has the potential to more effectively treat hematological malignancies.

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New anti-HER2 agents: from second-generation tyrosine kinases inhibitors to bifunctional antibodies

Purpose of review: HER2-positive breast cancers have benefited since the end of the twentieth century, not only from the improvement of biological knowledge, but also from major technological advances. The latter allowed the synthesis of the first generation of enzymatic inhibitors of the HER receptor family such as lapatinib, but above all, monoclonal antibodies such as trastuzumab or pertuzumab having profoundly modified the management of these cancers. However, despite outstanding progresses, there are still patients who are not cured with these first-generation treatments, and they will need new approaches to improve disease control and impact patients' survival. Recent findings: Understanding the mechanisms of escape to these treatments, more than real resistance, has profoundly changed our pharmacological approaches. They have enabled the development of molecules blocking the signaling pathway downstream of receptors such as mTOR, PI3K inhibitors or molecules interacting with the cellular traffic of the receptor in combination with the first-generation treatments. In addition, new second-generation tyrosine kinase inhibitors have demonstrated increased in-vitro efficacy, but still need to show clinical relevance because of new toxicity profiles. The antibody engineering had also permitted a paradigm evolution of the role of the antibody treatments, particularly with the synthesis of bispecific and trifunctional antibodies, promoting the link between the tumor and the immune system, with the goal to amplify the immune anticancer response. Summary: Among the new anti-HER2 agents, second-generation tyrosine kinase inhibitors and bifunctional antibodies are promising approaches that will help to improve disease control and curability of HER2-positive breast cancers.

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