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.