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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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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 the aggregation of activated platelets with cancer cells facilitates tumor metastasis; the adhesion molecule P-selectin may be an important mediator of this process, but the detailed mechanism is unclear. In the current study, we established a B16F10 (B16) cell metastatic model in P-selectin knockout (P-sel−/−) mice to determine the effect of P-selectin-mediated platelet adhesion on metastasis. Compared with C57 mice, P-sel−/− mice developed fewer metastatic foci, and cell proliferation within the metastatic tumors was inhibited by P-selectin deficiency. The platelet refusion assay demonstrated that mice with P-sel−/− platelets developed fewer lung metastatic foci (P<0.01) with a lower microvascular density (MVD) than mice with wild-type platelets. A co-culture model of platelets and B16 cells was utilized to determine the difference in VEGF concentration in the supernatants. The results demonstrated that the supernatant from the P-sel−/− platelet/B16 co-culture had a lower concentration of VEGF. Therefore, our findings indicated that P-selectin deficiency inhibited the metastasis of B16 cells and that wild-type platelet refusion reversed this inhibition. The P-selectin-mediated interaction between platelets and B16 cells promoted angiogenesis by up-regulating VEGF.

Gut microbiota metabolites have a great influence on host digestive function and body health itself. The effects of intestinal microbes on the host metabolism and nutrients absorption are mainly due to regulatory mechanisms related to serotonin, cytokines, and metabolites. Multiple studies have repeatedly reported that the gut microbiota plays a fundamental role in the absorption of bioactive compounds by converting dietary polyphenols into absorbable bioactive substances. Moreover, some intestinal metabolites derived from natural polyphenol products have more biological activities than their own fundamental biological functions. Bioactive like polyphenolic compounds, prebiotics and probiotics are the best known dietary strategies for regulating the composition of gut microbial populations or metabolic/immunological activities, which are called “three “p” for gut health”. Intestinal microbial metabolites have an indirect effect on atherosclerosis, by regulating lipid metabolism and inflammation. It has been found that the diversity of intestinal microbiota negatively correlates with the development of atherosclerosis. The fewer the variation and number of microbial species in the gut, the higher the risk of developing atherosclerosis. Therefore, the atherosclerosis can be prevented and treated from the perspective of improving the number and variability of gut microbiota. In here, we summarize the effects of gut metabolites of natural products on the pathological process of the atherosclerosis, since gut intestinal metabolites not only have an indirect effect on macrophage foaming in the vessel wall, but also have a direct effect on vascular endothelial cells.

Slit, a neuronal guidance cue, binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit has been reported to have an important effect on tumor growth and metastasis. In the current study, we evaluated the role of Slit2 in skin tumor growth and invasion in mice using a two-step chemical carcinogenesis protocol. We found that Slit2 expression correlated with the loss of basement membrane in the samples of human skin squamous cell carcinoma at different stages of disease progression. Slit2-Tg mice developed significantly more skin tumors than wild-type mice. Furthermore, the skin tumors that occurred in Slit2-Tg mice were significantly larger than those in the wild-type mice 10 weeks after 7,12-dimethylbenz[a]anthracene initiation until the end of the experiment. We also found that pathological development of the wild-type mice was delayed compared with that of Slit2-Tg mice. To further investigate the mechanism of increasing tumors in Slit2-Tg mice, we analyzed the expression of 5-bromo-2 0 -deoxyuridine (BrdU) in mouse skin lesions and found that the number of BrdU-positive cells and microvessel density in skin lesions were significantly higher in Slit2-Tg mice than in wild-type mice. Histological staining of PAS and type IV collagen and the colocalization of Slit2 and type IV collagen demonstrated varying degrees of loss of the basement membrane in the skin lesions from Slit2-Tg mice that were at the stage of carcinoma in situ. However, the basement membrane was well defined in the wild-type mice. In addition, MMP2, but not MMP9, was upregulated in the skin tissue of Slit2-Tg mice. Interruption of Slit2-Robo1 signaling by the antibody R5 significantly repressed the invasive capability of the squamous cell carcinoma cell line A431. Taken together, our findings reveal that Slit2 promotes DMBA/TPA-induced skin tumorigenesis by increasing cell proliferation, microvessel density, and invasive behavior of cutaneous squamous cell carcinoma, along with loss of basement membrane, by upregulation of MMP2 expression. Skin cancer is one of the most common malignant tumors. Approximately 2 to 3 million cases of nonmelanoma skin cancer occur annually worldwide, and its incidence has been rising rapidly over the past several decades. 1 Skin cancer develops through a multistage process that includes initiation, promotion, and progression, as shown in experimental animal models. 2 The two-stage murine skin carcinogenesis model, which comprises two distinctly separate stages (initiation and promotion), is one of the most well-established in vivo models of experimental carcinogenesis. After 7, anthracene (DMBA) initiation, repeated applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) promote papillomas and eventually carcinomas. 3 Slit, a member of neuronal guidance cues, has been implicated to play an important role in tumor progression. 4 The Slit family consists of three members (Slit1, Slit2, and Slit3) that are expressed in the nervous system, whereas Slit...

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