Abstract
Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.
Highlights
Pancreatic cancer is one of the malignant diseases with the worst prognosis
While soluble vascular cell adhesion molecule-1 (sVCAM-1) was detected at a similar level in control wild-type (WT) mice and PKF mice before the treatment, and was not increased after the treatment in WT mice, a robust increase of sVCAM-1 was observed in PKF mice 4 h after gemcitabine treatment, and the sVCAM-1 level further increased after 48 h of the treatment (Fig. 1B)
While it was reported that vascular cell adhesion molecule-1 (VCAM-1) expression in surgically resected pancreatic ductal adenocarcinoma (PDAC) tissue was associated with patient prognosis[31], VCAM-1 expression in tumor tissue is unknown in advanced pancreatic cancer
Summary
Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. (J) Bar graph showing relative quantification of Vcam[1] mRNA expression in murine PDAC cell lines cultured in control media or with gemcitabine (1 μM) for 24 h (n = 4 each). GEMMs have been broadly used for basic and translational research in this field because of their clinical relevance These mouse models display abundant desmoplastic changes in the pancreas, as seen in the microenvironment of human pancreatic cancer, are considered suitable for researches in the preclinical s ettings[11,12]
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