BMPs morph into new roles in ovarian cancer.

Comment on: Ma W, et al. Cell Cycle 2013; 12:88-97.

Our understanding of cancer pathogenesis is being revolutionized by the acceptance and continued molecular dissection of two central hypotheses of cancer biology. First, the “cancer stem cell” hypothesis is advancing our understanding of cancer progression and recurrence. Second, the “seed and soil” hypothesis defines a critical role for the tumor microenvironment in cancer growth and metastasis. In a recent issue of Cell Cycle, Ma et al. further define the interplay between these two hypotheses in ovarian cancer by demonstrating a regulatory link between the stem cell factor Lin28 and the signaling molecule bone morphogenic protein 4 (BMP4).

Lin28 is a stem cell factor that binds to and blocks downstream effects of the microRNA let-7, thus maintaining stem cell pluripotency. Several recent reports indicate that Lin28 is also an important factor in promoting tumorigenesis (Fig. 1). Lin28 was found to promote breast cancer growth via increased translation of the HER2 protein and to promote breast and ovarian cancer growth via increased expression of the cell cycle proteins CDK2, cyclin D1 and cell division cycle 25 homolog A (CDC25A). Ma et al. now demonstrate an additional tumorigenic role for Lin28. Lin28 binds to BMP4 at a newly identified Lin28-responsive element (LRE), leading to upregulation of BMP4 at the post-transcriptional level in epithelial ovarian cancer cells.

Figure 1. Lin28/BMP4 signaling pathways promote tumorigenesis. The newly defined regulatory role for Lin28 upregulating BMP4 (outlined arrow) adds to our understanding of Lin28 downstream signaling that promotes multiple aspects of the tumor phenotype (italics).

BMPs are members of the transforming growth factor-β (TGF-β) family of secreted peptides that function in both normal developmental tissue homeostasis and tumorigenesis. This current study adds to a growing literature supporting a critical role for BMPs in ovarian cancer by defining a potential autocrine function for BMPs expressed by cancer cells. We have previously reported a critical role for increased BMP2, BMP4 and BMP6 expression by mesenchymal stem cells in the tumor stroma. Increased BMP expression in the stroma increases the pool of cancer stem cells, resulting in enhanced tumorigenesis. BMP4 has also been shown to directly upregulate ID3 proto-oncogene expression in human ovarian cancer cells. Additionally, exogenous BMP4 treatment of ovarian cancer cells results in epithelial-mesenchymal transition (EMT), with increased cellular adhesion, motility and invasion. All of these studies support a pro-tumorigenic role of BMP overexpression in ovarian cancer (Fig. 1). These downstream effects of BMP signaling are consistent with the finding that overexpression of BMP2, a closely related family member of BMP4, is associated with poorer prognosis in ovarian cancer patients.

Ma et al. also extend the clinical implications of Lin28-mediated upregulation of BMP4 by looking at the prognostic implications of Lin28 overexpression. Immunohistochemical analysis of more than 300 primary ovarian cancers, looking at the expression of Lin28 and the stem cell factor Oct4, demonstrated that overexpression of Lin28 and Oct4 together is correlated with decreased patient survival. Interestingly, Lin28 and Oct4 define a subset of cells in ovarian cancer with stem-like properties. These findings, together with the role of BMPs in promoting ovarian cancer stemness, suggest an important interplay between Lin28/Oct4/BMP that impacts cancer stem cells, tumorigenesis and, ultimately, patient outcomes.

Ovarian cancer is a disease plagued by recurrences with progressive chemoresistance, ultimately leading to uncontrolled cancer growth resulting in patient death. The challenge that lies ahead is integrating our improved molecular understanding of ovarian cancer pathogenesis with novel therapeutic options to improve patient outcomes. Considering the BMP pathway, further studies are necessary to continue to tease out the relative roles of epithelial and stromal production of BMPs in ovarian cancer and the subsequent autocrine and paracrine effects of the aberrant BMP expression. Hopefully continued characterization of the newly identified Lin28/Oct4/BMP pathway will provide potential targeted therapy options for patients.