Abstract
The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer.
Highlights
Ovarian cancer is the most deadly US gynecologic malignancy, killing over 14,000 women yearly [1]
To determine if HH signaling is active in ovarian tumor stroma, we transplanted ID8 mouse ovarian tumor cells into the flank of Gli1lacZ mice. β-Gal as an indicator of HH signaling was clearly noted within the tumor stroma with significantly less β-Gal in adjacent non-tumor stroma (Figure 1Aii, iii)
To confirm HH signaling in human ovarian cancer, qRT-PCR of cDNA generated from primary human ovarian tumor samples were analyzed
Summary
Ovarian cancer is the most deadly US gynecologic malignancy, killing over 14,000 women yearly [1]. Most ovarian cancer patients will develop recurrent disease. Recurrent disease will become resistant to standard platinum-based chemotherapy leading to patient death. The tumor microenvironment is critical for the growth, spread and survival of cancer cells with emerging data describing the importance of stromal components such as adipocytes and cancer associated fibroblasts in ovarian cancer [2,3,4,5]. Mesenchymal stem cells (MSCs) are an important component of the tumor microenvironment [6, 7]. MSCs have been reported in a variety of other tissues including ovary, brain, spleen, liver, kidney, lung, muscle, thymus, pancreas, eyelid, and the peri-vasculature [11,12,13], suggesting MSCs may be present in many tissues throughout tumor initiation and growth
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