Inspite of doing extensive research work, cancer is still the leading cause of deaths. Its associated cost accounts a largest economic burden worldwide. Cancers are perhaps the most complicated diseases, since each tumor and/or a subpopulation of tumor cells may have a distinct type of genetic alteration, gene mutation, oncogenic signaling, metabolic features, epigenetic changes and also receive different multiple signals from local environment [1-7]. Cancer forming cells acquire many characteristics resembling to embryonic stem cells. For example, cancer initiating cells (cancer stem cells) and embryonic stem cells, both prefer glycolytic mechanism indicating a similar type of metabolic reprogramming [7,8]. Certain genetic alteration and the signals of tumor microenvironment may promote epigenetic switching which may be responsible for aggressiveness of cancers. Most poorly differentiated cancer cells express many embryonic transcription factors such as Snail, Twist, Zeb1, Sox2 and also modulate expressions of many microRNAs (such as miR-200c, miR-34a, miR-302-367, let-7a) which play crucial role in embryogenesis, and they undergo epithelial to mesenchymal transition (EMT) and regain at least in part their embryonic features [6,9,10]. Increased mesenchymal features in epithelial cancer cells make them more invasive, survival during transportation through blood circulation, extravasation from blood vessels, and survival at premalignant sites [6]. However, this increased mesenchymal characteristic does not support their growth at pre malignant sites, until they again undergo mesenchymal to epithelial transition (MET). In fact, disseminated cancer cells at premalignant site need to adjust with the new environment by accepting circumstantial signaling which may lead to develop a distinct type of epigenetic switching, resulting in conversion of EMT to MET, and eventually develop macro-metastasis [6]. Thus, dysregulation of such protein, which regulates embryogenesis or organogenesis may cause tumorigenesis and metastasis. Abnormal expressions of bone morphogenetic proteins (BMPs) which play critical role in embryogenesis, cartilage, and bone formation have been found in various types of cancers, which have been linked with tumorigenesis and metastasis of many cancer types [11-15]. However, the role of BMPs in tumorigenesis still remains a debate [16]. BMPs are a group of proteins which are known to be potent growth factors and morphogens of the TGFβ superfamily. BMPs transduce intracellular signaling cascades by both canonical and non-canonical pathways [12,17].

In canonical pathway, BMPs transduce their signals by binding with serine/threonine protein kinase receptors, followed by forming heterotetrameric complex of receptor type 1 and 2. This heterotetrameric complex when activated upon phosphorylation, phosphorylates regulatory receptor substrates R-Smads (Smad1, Smad5 and Smad8), which binds to co-Smad, Smad4 which also transduces TGFβ signaling, and subsequently undergoes nuclear translocation and regulate gene transcription with aid of other co-activator/co-repressor [12,17]. All BMPs usually mediate their signaling cascade following this basicmechanism. However, BMP-2 and BMP-4 first bind to receptor type I to make complex with receptor type II, whereas BMP-6 and BMP-7 first interact with type II to form complex by recruiting type I [12,18]. Therefore, these differences may generate distinct types of intracellular signaling. In non-canonical pathways, BMPs may activate various types of signaling such as PI3K/AKT, MAPKinase, p38 etc. [13,19-25]. Moreover, several signaling (e.g., Wnt signaling) cross talk to BMP pathway to modulate its functional activity [26]. Our earlier studies have established that BMP-2 activates PI3K/AKT signaling via ROS generation [20]. Moreover, shutting down of PI3K/AKT activity prevents BMP-2 driven Smad binding activity to the promoters of osterix and colony stimulating factor 1 (CSF1) to inhibit osteoblast and osteoclast activity respectively [21,22]. Thus, non-canonical signaling pathways work independently and also modulate the canonical pathway. Therefore, detail molecular understanding of BMP signaling is required to explain the functional activity of BMPs in various cell types including cancer cells.

Citation: Mandal C, Rahman M, Nag A (2015) An Update of Bone Morphogenetic Proteins as Biomarker and Therapy for Cancer. J Carcinog Mutagen 6:e114. doi: 10.4172/2157-2518.1000e114

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