Re-cycling paradigms: cell cycle regulation in adult hippocampal neurogenesis and implications for depression

Since adult neurogenesis became a widely accepted phenomenon, much effort has been put in trying to understand the mechanisms involved in its regulation. In addition, the pathophysiology of several neuropsychiatric disorders, such as depression, has been associated with imbalances in adult hippocampal neurogenesis. These imbalances may ultimately reflect alterations at the cell cycle level, as a common mechanism through which intrinsic and extrinsic stimuli interact with the neurogenic niche properties. Thus, the comprehension of these regulatory mechanisms has become of major importance to disclose novel therapeutic targets. In this review, we first present a comprehensive view on the cell cycle components and mechanisms that were identified in the context of the homeostatic adult hippocampal neurogenic niche. Then, we focus on recent work regarding the cell cycle changes and signaling pathways that are responsible for the neurogenesis imbalances observed in neuropathological conditions, with a particular emphasis on depression

Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts

<p>Abstract</p> <p>Background</p> <p>Combining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically.</p> <p>Methods</p> <p>Anti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation <it>in vivo</it>.</p> <p>Results</p> <p>RDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved <it>in vivo </it>are similar to those that produce target inhibition and cell cycle arrest <it>in vitro</it>.</p> <p>Conclusions</p> <p>Agents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients.</p

Role of LKB1 in lung cancer development

Three phenotypically related genetic syndromes and their lesions (LKB1, PTEN, and TSC1/2) are identified as frequently altered in lung cancer. LKB1, a kinase inactivated in 30% of lung cancers, is discussed in this review. Loss of LKB1 regulation often coincident with KRAS activation allows for unchecked growth and the metabolic capacity to accommodate the proliferation

Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer

Neoadjuvant and adjuvant chemotherapies provide survival benefits to breast cancer patients, in particular in estrogen receptor negative (ER-) cancers, by reducing rates of recurrences. It is assumed that the benefits of (neo)adjuvant chemotherapy are due to the killing of disseminated, residual cancer cells, however, there is no formal evidence for it. Here, we provide experimental evidence that ER- breast cancer cells that survived high-dose Doxorubicin and Methotrexate based chemotherapies elicit a state of immunological dormancy. Hallmark of this dormant phenotype is the sustained activation of the IRF7/IFN-beta/IFNAR axis subsisting beyond chemotherapy treatment. Upregulation of IRF7 in treated cancer cells promoted resistance to chemotherapy, reduced cell growth and induced switching of the response from a myeloid derived suppressor cell-dominated immune response to a CD4(+)/CD8(+) T cell-dependent anti-tumor response. IRF7 silencing in tumor cells or systemic blocking of IFNAR reversed the state of dormancy, while spontaneous escape from dormancy was associated with loss of IFN-beta production. Presence of IFN-beta in the circulation of ER- breast cancer patients treated with neoadjuvant Epirubicin chemotherapy correlated with a significantly longer distant metastasis-free survival. These findings establish chemotherapy-induced immunological dormancy in ER- breast cancer as a novel concept for (neo)adjuvant chemotherapy activity, and implicate sustained activation of the IRF7/IFN-beta/IFNAR pathway in this effect. Further, IFN-beta emerges as a potential predictive biomarker and therapeutic molecule to improve outcome of ER- breast cancer patients treated with (neo)adjuvant chemotherapy.Peer reviewe

Abstract P3-06-24: Early activation of IFN/STAT signaling in tumor cells of patient-derived triple negative breast cancer xenografts predicts tumor sensitivity to chemotherapy

Triple negative breast cancer (TNBC) is a tumor subtype characterized by the absence of overexpressed estrogen receptor-alpha (ER), progesterone receptor (PR), and HER2 receptor, encoded by ERBB2, a known proto-oncogene. This type of tumors account for approximately 15–25% of breast cancers at diagnosis, and is one of the most aggressive subtypes, with 77% of patients that live free of disease 5 years post-diagnosis. One of the most reliable predictive markers of patient outcome is the pathological complete response (pCR), which indicates that the surgical specimen removed after neoadjuvant chemotherapy contains no viable tumor cells detectable at histopathological level. For patients with pCR, the probability of surviving the disease is very high, however, pCR is observed only in about 20–30% of TNBC. On the other hand, for patients with no pCR the probablity of developing recurrent disease at 5 years is 50%. As pCR is strongly correlated with treatment efficacy, it is mandatory to develop methods that allow to tell as quick as possible if the treatment chosen for a given patient is efficiently working or if it should be abandoned in favor of an alternative strategy that could prove more efficacious. XenTech collection of breast cancer patient-derived xenografts (PDXs) includes 25 models of TNBC that display heterogeneous response to different chemotherapy agents. We used our models to investigate if transcriptional changes could be detected in PDXs that responded well to genotoxic agents. To do this we analyzed the gene expression profile of laser-microdissected residual tumor nodules interspersed in the murine stroma upon very efficient response to Adriamycin/Cyclophosphamide (AC). When doing so, we identified several genes of the IFN/STAT1 pathway that were over-expressed when compared to untreated tumors. This activation seems to be a transient event, as it was lost in tumors relapsing after the residual tumor nodule stage. The finding that residual cells from tumors strongly responding to AC treatment over-expressed IFN/STAT1 pathway-related genes prompted us to investigate whether this effect could be detected as an early event upon tumor exposure to chemotherapy. All TNBC models tested that were good responders to AC treatment displayed over-expression of IFN/STAT1 pathway-related genes as early as 3 days post-treatment, most of them reaching a plateau of intensity at day 7 post-treatment. By contrast, TNBC insensitive or low responders to AC treatment failed to show over-expression of IFN/STAT1 pathway-related genes. To verify if the selective over-expression of these genes in TNBC models sensitive to AC was independent of the treatment administered, Irinotecan and Capecitabine were used to treat TNBC models with heterogeneous response to these drugs. Again, we found that overexpression of IFN/STAT1 pathway-related genes was specifically identified at early stages only in TNBC models that responded well to these drugs. These results suggest that genes of the IFN/STAT1 pathway could be early predictors of tumor response in patients receiving neoadjuvant chemotherapy. Prospective clinical validation studies are warranted to confirm the findings from this preclinical study

MUC1, MUC2, MUC4, MUC5AC and MUC6 expression in the progression of prostate cancer

Molecular changes are vital for the development of prognostic markers and therapeutic modalities of prostate cancer (CaP). There is growing interest in mucins as treatment targets in human malignancies, including CaP. The role of their expression in the progression of CaP is however unclear. We examined the expressions MUC1, MUC2, MUC4, MUC5AC and MUC6 in CaP tissues using tissue microarrays (TMAs) to look for tumor-associated antigens (TAAs) for targeted therapy. In this study, 120 paraffin-embedded specimens were selected from patients who underwent radical retro-pubic prostatectomy (RRP) or trans-urethral-resection of the prostate (TURP) for primary, untreated CaP and 10 matched lymph node metastases. A series of MUC monoclonal antibodies (mAbs) was used on TMAs by standard immunohistochemistry. Our results indicate that the over-expression of MUC1 was detected in 58% of primary CaP tissues and 90% of lymph node metastases but not in normal prostate or benign tissues, while the expression of MUC2, MUC4, MUC5AC and MUC6 was found to be negative in both normal and cancer tissues. Of the MUC1 positive tumors 86% were Gleason grade 7 or higher. Over-expression of MUC1 was found in late stage CaP while MUC2, 4, 5AC and 6 were negative in CaP. MUC1 is a TAA that is highly related to tumor progression in CaP patients. This antigen is ideal for targeted therapy to control micrometastases and hormone refractory disease but additional studies are necessary to assess its usefulness in patient biopsies and CaP bone metastases before clinical trial