Modulation Of Thrombospondin-1 In The Lung Microenvironment: Implications For Targeting Metastasis

Abstract

Metastasis of cancer to distant organs is the major cause of its lethality. With recent studies highlighting the role of the premetastatic niche in supporting metastatic progression, we focused our efforts on understanding the interplay between reprogrammed microenvironments in distal organs and tumor cells, to determine novel mechanisms that contribute to metastasis progression and identify potential targets for metastasis suppression. Our investigations unraveled a critical role of the anti-tumorigenic factor thrombospondin-1 (Tsp-1) in the reprogrammed lung microenvironment. Premetastatic niches generated in the lungs by metastasis-incompetent primary tumors showed elevated Tsp-1 expression. Interestingly, Gr1+ myeloid cells in the lungs were the major producers of Tsp-1, and they responded to the tumor-derived factor prosaposin (psap), abundantly secreted by metastasis-incompetent tumors compared to their metastatic counterparts. Further analysis led to the identification of the pentapeptide sequence, DWLPK, within psap that retains Tsp-1-inducing activity. Using DWLPK, recapitulated Tsp-1 induction in Gr1+ cells in the lungs and suppressed metastasis of Lewis lung carcinoma cells. These results suggest that DWLPK can potentially serve as a therapeutic agent for metastasis suppression. Studying metastasis in the setting of pre-existing lung inflammation, we observed loss of Tsp-1 in the lung microenvironment. Intranasal administration of bacterial lipopolysaccharide (LPS) induced lung inflammation, characterized by recruitment of Ly6G+ neutrophils, and it enhanced metastatic burden. Inflammation was accompanied by an increase in neutrophil elastase (NE) and cathepsin G (CG) protease activity, and loss of Tsp-1 protein in lungs. Our studies confirmed that NE and CG degrade Tsp-1 in lungs in response to LPS-induced inflammation, thus promoting metastasis. Interestingly, blocking the neutrophil proteases pharmacologically using the dual protease inhibitor Sivelestat suppressed metastasis, indicating that the proteases are clinically viable anti-metastatic therapeutic targets. Our studies demonstrate the novel finding that metastasis-incompetent tumors render the distal site metastasis-suppressive, by systemically inducing Tsp-1 expression in recruited myeloid cells. On the other hand, we have described a novel mechanism, where inflammation leads to Tsp-1 degradation via neutrophil proteases, generating a metastasis-promoting microenvironment. Our findings highlight the context-dependent plasticity of Ly6G+ cells at distal sites, functioning as the main source of anti-tumorigenic Tsp-1 and the proteases that degrade it