Interaction of Cancer Stem Cells and the Tumor Microenvironment Regulates Growth and Progression of Ovarian Tumors

Recently published findings on the interaction of the growth factors Lin28, Oct4, and BMP4 unite two basic theories of how tumors develop and progress.

LIN28 is a marker of undifferentiated human embryonic stem cells and has been used to enhance the efficiency of the formation of induced pluripotent stem (iPS) cells from human fibroblasts. It is a microRNA-binding protein that binds to and enhances the translation of the IGF-2 (insulin-like growth factor 2) mRNA. Lin28 has also been shown to bind to the let-7 pre-microRNA and block production of the mature let-7 microRNA in mouse embryonic stem cells. In pluripotent embryonal carcinoma cells, LIN28 is localized in the ribosomes, P-bodies, and stress granules.

BMP4 is a polypeptide belonging to the TGF-beta (transforming growth factor beta) superfamily of proteins. It, like other bone morphogenetic proteins, is involved in bone and cartilage development, specifically tooth and limb development and fracture repair. This particular family member plays an important role in the onset of endochondral bone formation in humans. It has been shown to be involved in muscle development, bone mineralization, and ureteric bud development.

Oct-4 (octamer-binding transcription factor 4) also known as POU5F1 (POU domain, class 5, transcription factor 1) is a protein that in humans is encoded by the POU5F1 gene. This protein is critically involved in the self-renewal of undifferentiated embryonic stem cells, and, as such, it is frequently used as a marker for undifferentiated cells.

Investigators at Yale University (New Haven, CT, USA) reported in the January 1, 2013, issue of the journal Cell Cycle that elevated production of BMPs from human ovarian cancer cells and stroma increased cancer stem cell proliferation and tumor growth. The stem cell factor Lin28 bound to BMP4 mRNA in epithelial ovarian carcinoma cells, thereby promoting BMP4 expression at the post-transcriptional level.

As coexpression of Lin28 and Oct4 (another stem cell factor) had been implicated in ovarian cancer stem cells, the investigators also determined that high levels of Lin28 were associated with an unfavorable prognosis when coexpressed with high levels of Oct4. Together, these findings uncovered a new level of regulation of BMP4 expression and implied a novel Lin28/Oct4/BMP4-mediated mechanism of regulating ovarian tumor cell growth, thus holding potential for the development of new strategies for the diagnosis and treatment of ovarian cancer.

The finding that Lin28 and Oct4 (both stem cell factors) regulated BMP-4 united two theories related to how cancer stem cells and the tumor microenvironment interact to promote tumor growth and progression.

"Ovarian cancer patients are plagued by recurrences of tumor cells that are resistant to chemotherapy, ultimately leading to uncontrolled cancer growth and death," said senior author Dr. Yingqun Huang, associate professor of obstetrics, gynecology, and reproductive sciences at Yale University. "These results are supported by the latest molecular ovarian cancer prognosis data, which also suggest an active role for the tumor microenvironment in ovarian carcinogenesis. "Together these studies reveal new targets for the development of cancer therapies."

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