Abstract
Interrupting the interplay between cancer cells and extracellular matrix (ECM) is a strategy to halt tumor progression and stromal invasion. Perlecan/heparan sulfate proteoglycan 2 (HSPG2) is an extracellular proteoglycan that orchestrates tumor angiogenesis, proliferation, differentiation and invasion. Metastatic prostate cancer (PCa) cells degrade perlecan-rich tissue borders to reach bone, including the basement membrane, vasculature, reactive stromal matrix and bone marrow. Domain IV-3, perlecan’s last 7 immunoglobulin repeats, mimics native proteoglycan by promoting tumoroid formation. This is reversed by matrilysin/matrix metalloproteinase-7 (MMP-7) cleavage to favor cell dispersion and tumoroid dyscohesion. Both perlecan and Domain IV-3 induced a strong focal adhesion kinase (FAK) dephosphorylation/deactivation. MMP-7 cleavage of perlecan reversed this, with FAK in dispersed tumoroids becoming phosphorylated/activated with metastatic phenotype. We demonstrated Domain IV-3 interacts with the axon guidance protein semaphorin 3A (Sema3A) on PCa cells to deactivate pro-metastatic FAK. Sema3A antibody mimicked the Domain IV-3 clustering activity. Direct binding experiments showed Domain IV-3 binds Sema3A. Knockdown of Sema3A prevented Domain IV-3-induced tumoroid formation and Sema3A was sensitive to MMP-7 proteolysis. The perlecan-Sema3A complex abrogates FAK activity and stabilizes PCa cell interactions. MMP-7 expressing cells destroy the complex to initiate metastasis, destroy perlecan-rich borders, and favor invasion and progression to lethal bone disease.
Highlights
The physical border perlecan stabilizes, and potentially releasing growth factors and exposing cryptic bioactive motifs within perlecan[8]
To determine if this was a property of intact perlecan as seen by prostate cancer (PCa) cells, heparan/chondroitin sulfate containing full length human perlecan was purified from natural sources (HT29 cell conditioned media)[28] and coated onto cell culture plates
This reiterates that the protein core is responsible for the effect. These findings demonstrate that intact perlecan’s cell clustering effect is completely reversed upon enzymatic digestion of GAG chains or upon proteolysis by matrix metalloproteinase-7 (MMP-7) to favor loss of cell-cell adhesion, increase in cell substratum adhesion and favor tumor dyscohesion and dispersion. We found that another bone metastatic but osteolytic prostate cancer cell line, PC3, did not cluster nearly as well as C4-2B cells when plated onto Domain IV-3 substrata
Summary
The physical border perlecan stabilizes, and potentially releasing growth factors and exposing cryptic bioactive motifs within perlecan[8]. The tendency to form spheroids is dramatically reversed by MMP-7 cleavage of perlecan, allowing cells to disperse[9], which mimics invasive cell activity in the tumor microenvironment. It is not known how PCa cells respond to perlecan in the native tissue environment, nor is it known how cells recognize the presence of perlecan at tissue borders. Given its influence in development and homeostasis, we sought to determine if any of various semaphorins and plexins in PCa cells interact with perlecan and by doing so influence cancer invasion and metastasis[23,24,25,26]
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