Abstract
Abstract Background: Platelets are promoters of cancer cell proliferation at the metastatic niche, however the exact mechanism(s) by which platelets drive cancer cell proliferation remain ill-defined. The oncoprotein c-MYC, which governs neoplastic proliferation, is overexpressed in pancreatic tumors at the metastatic site as compared to primary tumors, with the overexpression of c-MYC indicative of a poor clinical outcome for patients with cancer. At present, the oncogenic pathways mediating c-MYC upregulation in metastatic cancer cells are largely unknown. Our exciting preliminary data demonstrate for the first time that platelets upregulate c-MYC protein levels in PANC-1 pancreatic cancer cells, suggesting a novel prometastatic role for platelets in pancreatic cancer. Aims: To define the mechanisms by which platelets upregulate c-MYC protein levels in PANC-1 pancreatic cancer cells. Methods: We utilized a co-culture platform to examine the effect of resting and thrombin-stimulated human platelets as well as platelet fractions (platelet-derived membrane bound molecules and soluble molecules) on c-MYC expression in PANC-1 cancer cells. Platelet inhibitors, including the GPIIbIIIa blocker Integrilin, were used to study the molecular mechanisms by which platelets upregulate c-MYC expression in cancer cells. Changes in c-MYC oncoprotein were detected by Western Blotting. The physical association between platelets and PANC-1 cancer cells was quantified by immunoblotting with an anti-GPIIb antibody against the platelet-specific integrin GPIIbIIIa. Results: Resting and activated platelets as well as platelet fractions induced an upregulation of c-MYC expression in PANC-1 cancer cells. The effect of platelets on c-MYC expression was largely dependent on direct contact with the cancer cells, as the preincubation of platelets with Integrilin reduced platelet-induced c-MYC expression. Conclusion: We show that the expression of c-MYC in PANC-1 cancer cells can be upregulated by platelets, revealing a novel mechanism of platelet action in the progression of cancer and suggesting that the overexpression of c-MYC at the metastatic niche may be inhibited through the use of platelet inhibitors. We are currently characterizing the molecular underpinnings of platelet-mediated c-MYC regulation with respect to the contribution of platelets to cancer cell proliferation and growth. Citation Format: Annachiara Mitrugno, Katherine Pelz, Rosalie Sears, Owen McCarty. Role of the blood microenvironment in the upregulation of oncoproteins in circulating pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B62.
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