Platelets increase survival of adenocarcinoma cells challenged with anticancer drugs: mechanisms and implications for chemoresistance

Abstract

BACKGROUND AND PURPOSECancer cells grow without the restraints of feedback control mechanisms, leading to increased cancer cell survival. The treatment of cancer is often complicated by the lack of response to chemotherapy leading to chemoresistance and persistent survival of tumour cells. In this work we studied the role of platelets in chemotherapy-induced cancer cell death and survival. EXPERIMENTAL APPROACHHuman adenocarcinoma cells, colonic (Caco-2) and ovarian (59 M) cells, were incubated with 5-fluorouracil (1-300 mg·mL ) for 1, 24 or 72 h. Following incubation, cancer cells were harvested and cell survival/death was assayed using flow cytometry, Western blotting, real-time PCR, TaqMan® Gene Expression Assays and proteomics. KEY RESULTSHuman platelets increased the survival of colonic and ovarian adenocarcinoma cells treated with two standard anticancer drugs, 5-fluorouracil and paclitaxel. In the presence of platelets, cancer cells up-regulated anti-apoptotic and down-regulated pro-apoptotic genes, increased the number of cells in the synthesis of DNA and decreased the number in the quiescent phase, increased expression of cyclins, DNA repair proteins and MAPKs. The analysis of platelet-Caco-2 secretome demonstrated the release of the chemokine RANTES, thrombospondin-1, TGF-b and clusterin. Finally, human recombinant RANTES and thrombospondin-1 improved survival of Caco-2 cells challenged with paclitaxel. CONCLUSIONS AND IMPLICATIONSThese data demonstrate that platelets increase adenocarcinoma cells survival, proliferation and chemoresistance to standard anticancer drugs. Modulating cancer cell-platelet interactions may offer a new strategy to improve the efficacy of chemotherapy. Abbreviations59 M, human ovarian adenocarcinoma; 5-FU, 5-fluorouracil; Caco-2, human colonic adenocarcinoma; Chk1, checkpoint 1; CRL2014, human gingival fibroblasts; G0/G1, quiescent/interphase G1 phases; G2/M, interphase G2/mitosis phases; PI, propidium iodide; PLT, platelets; PLTR, platelets releasate; PTX, paclitaxel; S, synthesis phase; TCIPA, tumour cell-induced platelet aggregation; TSP-1, thrombospondin-1

Platelets surrounding primary tumor cells are related to chemoresistance

“…Patients whose pre-treatment biopsy specimens contained platelets surrounding tumor cells at a rate >10% of the total number of tumor cells showed significant residual cancer cells in surgical specimens following chemotherapy. Recent reports have demonstrated that human platelets increase cancer cell survival, proliferation, and chemoresistance to 5-fluorouracil and paclitaxel in colon and ovarian cancer in vivo (27). Moreover, chemoresistance could be induced by platelets throughout EMT (28), PAI-1-mediated anti-apoptotic pathways, direct protection, or immunosuppression mediated by downregulation of NKG2-D (29,30).…”

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

“…Platelets seem to be of special importance for metastasis, since thrombocytosis is frequently observed in patients with metastatic cancers [58] . Platelets facilitate invasion of cancer cells, intra-and extravasation of CTCs (by secreting lysophosphatidic acid) [59,60] , protect them from various host attacks, such as immune assaults [61,62] , apoptosis [63,64] and shear stress [57,65,66] . Importantly, platelets may also contribute to EMT of CTCs and more efficient metastases formation [67] .…”

High Platelet Levels Attenuate the Efficacy of Platinum-Based Treatment in Non-Small Cell Lung Cancer

“…However, they are also involved in many non-hemostatic functions, including tissue repair [1] , inflammation [2], lymphatic development, and angiogenesis [3]. Platelets also boost cancer metastasis and cell proliferation by pericellular adhesion and signal transduction [4][5][6]. Such pleiotropic effects are possible due to the numerous molecules released from activated platelets.…”