Involvement of Platelet–Tumor Cell Interaction in Immune Evasion. Potential Role of Podocalyxin-Like Protein 1

Abstract

Besides their essential role in hemostasis and thrombosis, platelets are involved in the onset of cancer metastasis by interacting with tumor cells. Platelets release secretory factors that promote tumor growth, angiogenesis, and metastasis. Furthermore, the formation of platelet–tumor cell aggregates in the bloodstream provides cancer cells with an immune escape mechanism by protecting circulating malignant cells from immune-mediated lysis by natural killer (NK) cells. Platelet–tumor cell interaction is accomplished by specific adhesion molecules, including integrins, selectins, and their ligands. Podocalyxin-like protein 1 (PCLP1) is a selectin-ligand protein in which overexpression has been associated with several aggressive cancers. PCLP1 expression enhances cell adherence to platelets in an integrin-dependent process and through the interaction with P-selectin expressed on activated platelets. However, the involvement of PCLP1-induced tumor–platelet interaction in tumor immune evasion still remains unexplored. The identification of selectin ligands involved in the interaction of platelets with tumor cells may provide help for the development of effective therapies to restrain cancer cell dissemination. This article summarizes the current knowledge on molecules that participate in platelet–tumor cell interaction as well as discusses the potential role of PCLP1 as a molecule implicated in tumor immune evasion.

Cancer and Thrombosis: The Platelet Perspective

“…L-selectin on leukocytes acts synergistically with P-selectin, facilitating platelet-tumor interaction (Borsig et al, 2002). Podocalyxin-like protein 1 (PCLP1) binds E- and L-selectin in pancreatic cancer (Dallas et al, 2012), and is overexpressed in many cancers and on activated platelets (Amo et al, 2014). Once activated, platelets can then bind to tumor cells via P-selectin (Chen and Geng, 2006; Coupland et al, 2012; Qi et al, 2015) and glycoproteins (Lonsdorf et al, 2012; Goubran et al, 2013) and directly induce tumor growth and metastasis by releasing pro-tumor angiogenic and growth factors.…”

“…Platelets and platelet-derived microparticles adhere to tumor cells through interactions with integrins and selectins (Kitagawa et al, 1989; Felding-Habermann et al, 1996; Gay and Felding-Habermann, 2011). Additionally, fibronectin and other adhesive molecules may act as a bridge between platelets and tumor cells, as mediated by PCLP1 (Amo et al, 2014). Tumor cells are enshrouded in platelet-fibrin mesh, shielding them from NK cell contact and immune surveillance in circulation (Borsig et al, 2001).…”

Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer

“…There is growing evidence suggesting the co-operative behaviour exhibited by cells within CTMs can promote mutual survival and increased tumorigenic potential (16,33,(141)(142)(143)(144). It has also been suggested that interactions between blood cell and platelets can benefit both CTMs and single CTCs by protecting them from the host immune system (134,(145)(146)(147). Cellular cooperation has been elegantly demonstrated using a model derived from hamster oral keratinocytes of both mesenchymal and epithelial cells (148).…”

Endothelium and cancer metastasis: Perspectives for antimetastatic therapy

“…In fact, in such clusters, migrating malignant cells are surrounded by a platelet shield that may provide mechanical protection from physical damages. Moreover, activated platelets may facilitate tumor cell survival utilizing TGF-b or PDGF-related signaling pathways resulting in the inhibition of the effector functions of natural killer cells [63,64] or may mask tumor cells, and thus prevent their recognition by natural killer cells [65][66][67]. Accordingly, inhibition of platelet activity results in the enhanced cytotoxic activity of natural killer cells [68].…”