Heparan sulfate modifiers and signaling between tumor-associated macrophages and cancer-associated fibroblasts in a biomimetic hydrogel model of bone-metastatic prostate cancer

The establishment of a new tumor niche for most carcinomas is orchestrated primarily by the bidirectional engagement of cancer cells and fibroblasts. Cancer cells reprogram and activate fibroblasts into a wound healing-like state and, in turn, these cancer-associated fibroblasts (CAFs) react by remodeling the extracellular matrix (ECM) and secreting chemokines and growth factors. Macrophages are rapidly recruited to the tumor and represent the primary immune cell in the microenvironment. Tumor-associated macrophages (TAMs) enter a wound healing-like loop, displaying the full spectrum of macrophage phenotypes and behaviors as the disease progresses. Among these activities is the ability to modulate growth factor bioavailability. Deposition of the heparan sulfate (HS) proteoglycan perlecan/HSPG2 in the ECM and secretion of HS modulators are increased as result of the cancer-CAF-TAM trialogue and play critical roles in the availability and signaling of growth factors, cytokines, and chemokines. In this work, we developed a novel, biomimetic 3D hydrogel system composed of hyaluronic acid and collagen I (1:1) to study prostate cancer bone metastases. Our goal was to explore the molecular signaling between TAMs and CAFs to learn how this interaction affects the expression of the enzymes that modulate HS as a growth factor depot. Essential modulators of HS include heparanase (HPSE) and sulfatases 1 and 2 (SULF1, 2), all of which selectively release growth factors to influence signaling in the tumor microenvironment. We found that alternatively activated macrophages (M2) and TAMs (M2-like) increase levels of HPSE and SULFs in CAFs. We next examined the impact of TAM-CAF co-signaling on prostate cancer viability, growth, and dependence on HS modulators. Our data show that as a consequence of the TAM-CAF interaction, the elevated levels of HS-modifying enzymes are sufficient to trigger substantial changes in prostate cancer cell behavior, including viability, proliferation, and response to growth factors. We currently are assessing if these outcomes are seen in a series of patient-derived prostate xenograft lines representing different prostate cancer subtypes. We conclude that our 3D hydrogel model is a physiologically relevant in vitro system to discover fundamental aspects of HS signaling in the tumor microenvironment and thus uncover new ways to reduce the bioavailability of growth factors in the prostate cancer microenvironment and interfere with cancer progression. (Supported by NIH P01 and CAPES.) Citation Format: Fabio Henrique Brasil da Costa, Nora M. Navone, Mary C. Farach-Carson, Daniel D. Carson. Heparan sulfate modifiers and signaling between tumor-associated macrophages and cancer-associated fibroblasts in a biomimetic hydrogel model of bone-metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3799.