Some solid tumors are characterized by extracellular matrix (ECM) remodeling and stiffening, which is related to solid tumor progression and aggression. However, the relationship between ECM stiffness and colorectal cancer (CRC) remains unclear. In this study, we investigated the relevance of ECM stiffness to clinicopathologic features using human CRC tissue microarrays. The results demonstrate that the expression of ECM components in CRC tissues is closely correlated with CRC progression and poor prognosis, which indicates that ECM stiffness may be associated with CRC development. We further studied lysyl oxidase (LOX) expression in CRC tissue and demonstrated that LOX expression is closely correlated with CRC progression. Previous studies showed that P-selectin-mediated platelet accumulation in CRC tissue may up-regulate LOX expression. Our findings indicate that P-selectin-mediated platelet aggregation may up-regulate LOX expression and enhance the remodeling and stiffening of the tumor ECM, which may promote the progression of colorectal cancer. Therefore, LOX may be a potential effective therapeutic target to treat colorectal cancer.

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Blood platelets foster carcinogenesis. We found that platelets are accumulated in human tumors. P-selectin deficiency and soluble P-selectin abolish platelet deposition within tumors, decreasing secretion of vascular endothelial growth factor and angiogenesis, thereby suppressing tumor growth. Binding of the P-selectin cytoplasmic tail to talin1 triggers the talin1 N-terminal head to interact with the β3 cytoplasmic tail. This activates αIIbβ3 and recruits platelets into tumors. Platelet infiltration into solid tumors occurs through a P-selectin-dependent mechanism.

Studies have indicated that platelets play an important role in tumorigenesis, and an abundance of platelets accumulate in the ovarian tumor microenvironment outside the vasculature. However, whether cancer cells recruit platelets within intestinal tumors and how they signal adherent platelets to enter intestinal tumor tissues remain unknown. Here, we unexpectedly found that large numbers of platelets were deposited within human colorectal tumor specimens using immunohistochemical staining, and these platelets were fully associated with tumor development. We further report the robust adhesion of platelet aggregates to tumor cells within intestinal tumors, which occurs via a mechanism that is dependent on P-selectin (CD62P), a cell adhesion molecule that is abundantly expressed on activated platelets. Using spontaneous intestinal tumor mouse models, we determined that the genetic deletion of P-selectin suppressed intestinal tumor growth, which was rescued by the infusion of wild-type platelets but not P-selectin-/- platelets. Mechanistically, platelet adhesion to tumor cells induced the secretion of vascular endothelial growth factor (VEGF) to promote angiogenesis and accelerate intestinal tumor cell proliferation. Our results indicate that the adherence of platelets to tumor cells could promote tumor growth and metastasis. By targeting this platelet-tumor cell interaction, recombinant soluble P-selectin may have therapeutic value for the treatment of intestinal tumors.

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