BMP7v induces cancer stem cells differentiation and enhances chemotherapy response in colorectal cancer

Cancer stem cells (CSCs), characterized by high levels of ATP-binding cassette, anti-apoptotic molecules, active DNA-repair and slow replication capacities, surviving to conventional anti-cancer therapies, able to eradicate only the highly proliferating tumor cells, represent the elective target for new therapies. Colorectal CSCs (CR-CSCs) represent a powerful tool for preclinical validation of target therapies. In particular the elucidation of the mechanisms that govern stem cell survival and differentiation appears very essential for the identification of new molecular targets in cancer therapy. Among the molecules that govern these processes there are the Bone Morphogenetic Proteins (BMPs), members of the TGF-b superfamily. Here we propose that a BMP7 variant (BMP7v) have an important antitumoral and anti angiogenetic effect on CR-CSCs inducing a differentiation program and making these cells more sensitive to conventional chemotherapy drugs. BMP7v in vitro administration, activates the BMP signaling pathway in CR-CSCs, reducing the percentage of stem cell marker expression and enhancing epithelial colonic differentiation marker expression. BMP7v reduces self-renewal of CR-CSCs inducing their exit from quiescence and, reducing their typical mesenchymal trait, decreases their invasive and endothelial cord formation capacity. In vivo, BMP7v decreases tumor growth and stem cell marker expression, enhancing differentiation compared with control mice and in combination with CRC standard chemotherapy reduces tumor growth, inducing a differentiative and antiproliferative effect, associated with a strong antiangiogenic role. In addition, BMP7v as second-line of treatment also showed a significant anti-tumor activity in xenografts refractory to chemotherapy. Our data support the use of BMP7v as differentiative agent in combination with cytotoxic drugs for the treatment of CRC, and the use of BMP7v provides a potentially powerful and novel approach for the treatment of tumor disease

Cancer Stem Cells Sensitivity Assay (STELLA) in Patients with Advanced Lung and Colorectal Cancer: A Feasibility Study.

Cancer stem cells represent a population of immature tumor cells found in most solid tumors. Their peculiar features make them ideal models for studying drug resistance and sensitivity. In this study, we investigated whether cancer stem cells isolation and in vitro sensitivity assay are feasible in a clinical setting. METHODS: Cancer stem cells were isolated from effusions or fresh cancer tissue of 23 patients who progressed after standard therapy failure. Specific culture conditions selected for immature tumor cells that express markers of stemness. These cells were exposed in vitro to chemotherapeutic and targeted agents. RESULTS: Cancer stem cells were extracted from liver metastases in 6 cases (25%), lung nodules in 2 (8%), lymph node metastases in 3 (12.5%) and pleural/peritoneal/pericardial effusion in 13 (54%). Cancer stem cells were successfully isolated in 15 patients (63%), including 14 with lung cancer (93.3%). A sensitivity assay was successfully performed in 7 patients (30.4%), with a median of 15 drugs/combinations tested (range 5-28) and a median time required for results of 51 days (range 37-95). CONCLUSION: The approach used for the STELLA trial allowed isolation of cancer stem cells in a consistent proportion of patients. The low percentage of cases completing the full procedure and the long median time for obtaining results highlights the need for a more efficient procedure. TRIAL REGISTRATION: ClinalTrials.gov NCT01483001

CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis

Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6- progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target. © 2014 Elsevier Inc