Platelets enhance malignant behaviours of gastric cancer cells via direct contacts

Abstract

In this study, we aimed to analyse human cancer cell–platelet interactions in functional cell analyses and explore the molecular mechanisms behind tumour progression. Various functional analyses of gastric cancer (GC) cells were performed after direct/indirect co-incubation with platelets derived from GC patients. Further detailed expression and signalling analyses were performed after co-culture with direct and indirect GC cells–platelet contact. Malignant behaviours of cancer cells, such as proliferation, migration, invasion and adhesion, were significantly enhanced after direct co-incubation with platelets. Microarray analyses demonstrated changes in multiple genes, including epithelial–mesenchymal transition (EMT)-related genes. Among them, matrix metalloproteinase 9 was notably upregulated, which was validated by quantitative reverse transcription–polymerase chain reaction and western blot. Further, this change was only observed after direct co-incubation with platelets. This study demonstrated that platelets from GC patients promote malignant behaviours of GC cells through EMT-related signalling, especially by direct contact with tumour cells.

Platelet Membrane: An Outstanding Factor in Cancer Metastasis

“…Another more recent study demonstrated that direct contact between platelets isolated from patients with advanced gastric cancer and gastric cancer tumor cells induced processes of migration, invasion, adhesion, and expression of MMP9 in tumor cells [217]. Extravasated platelet aggregates have been evidenced in invasive parts of clinical samples from human pancreatic cancer biopsies.…”

“…These aggregates are associated with markers for the first steps of EMT, such as increased expression of Snail1 and reduced E-cadherin. Ishikawa et al reported that in 60% of the samples from a Japanese cohort of patients with HER2 negative breast cancer (biopsy samples), platelets were found directly surrounding the primary tumor cells, and that these tumor cells showed the expression of EMT markers [217].…”

“…Once CTCs have managed to survive in the circulatory system with the help of platelets, they must fulfill the objective of creating metastatic foci, so they must leave the blood system and seed a second metastatic tumor [217][218][219][220][221][222][223]. Platelets stimulate extravasation by releasing ATP from their dense granules upon activation, which modulates endothelial junctions and the endothelial cytoskeleton to induce a breakdown of the endothelial barrier [223].…”

The Role of Platelet Cell Surface P-Selectin for the Direct Platelet-Tumor Cell Contact During Metastasis Formation in Human Tumors

“…These facts indicate that tumor cells in the first phase of metastasis depend on at least two signals from platelets (through direct and indirect tumor/platelet contact), whereby signal transmission through platelet-cell contact is mandatory for metastasis formation. Accordingly, a recent study has shown that direct contact between platelets isolated from advanced gastric cancer patients and gastric cancer cells particularly induced migration, invasion, adhesion, and MMP9 expression in the tumor cells (54).…”

Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies

“…Cancer metastasis consists of an invasion-metastasis cascade, namely, tumor cells firstly exit their primary growth sites, survive in the circulation, extravasate at distant organ site, and lastly proliferate in the foreign microenvironments ( 144 ). Tumor cell-educated platelet (TEPs) participated in multiple steps of metastasis, helping the “villain” to do evil ( 134 , 145 ). Blocking platelet activation ( 146 ) or in the absence of platelets ( 147 ), cancer metastasis was markedly repressed.…”