Abstract
Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1's role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs.
Highlights
Prostate cancer (PCa) is the most common and second leading cause of cancer-related deaths among men [1]
We found that the mRNA levels of SULF1 were 150 to 200 times higher in HS27As and bone marrow stromal cells (BMSCs) compared to PCa cells and macrophages (Fig 1A), while SULF2 mRNA levels were both substantially lower and similar across all cell types tested (Fig 1B)
When comparing the levels of each mRNA in bone marrow fibroblasts, we noted that SULF1 mRNA levels were approximately 12-fold and 50-fold higher than those of HPSE and SULF2 in HS27A cells, respectively; and nearly 60 fold and 30 fold higher than HPSE and SULF2 in BMSCs, respectively (S1 Fig)
Summary
Prostate cancer (PCa) is the most common and second leading cause of cancer-related deaths among men [1]. PCa demonstrates metastatic tropism for bone marrow; over 80% of PCa patients who succumb to disease harbor bone metastases at autopsy [2]. Multiple lines of evidence support a role for stromal and immune cells in the transition of PCa from indolent to lethal phenotype [4, 5]. A dynamic cross-talk between PCa cells, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs) impacts cancer behavior and disrupts normal tissue homeostasis [6,7,8,9]. The landscape of macrophage infiltration and phenotype in bone metastases of PCa has been explored in murine disease models [12] and tissue specimens from warm biopsy specimens [13], but never in a human biomimetic system where macrophages can directly interact with PCa and fibroblastic stromal cells simultaneously
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