Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium-specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2 KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2 KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2 KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC. IntroductionPancreatic cancer is the fourth and fifth leading cause of cancer death in the United States and Japan, respectively (1, 2). It is one of the most lethal cancers, with 5-year survival rate of less than 5% that is partially attributed to the difficulty of early diagnosis. Moreover, even with a successful resection, 5-year survival is still less than 20%. The poor outcome after resection may be due to the frequent aggressive character of pancreatic tumor cells, which are often able to efficiently invade, disseminate, and metastasize (3, 4).The most common type of human pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). Previous studies have suggested a multistep progression model of PDAC that includes a preinvasive state termed pancreatic intraepithelial neoplasia (PanIN). PDAC is thought to result from progression of PanIN lesions through accumulation of specific genetic alterations (5). Activation of a point mutation of the KRAS proto-oncogene and inactivation of tumor suppressor genes, including P16 INK4A , P53, and SMAD4 (also known as deleted in pancreatic adenocarcinoma 4 [DPC4]), have been shown to increase in frequency with progression of the PanIN stages. Notably, at the invasive stage, the mutations and deletions

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

“…Previous reports have also described CTGF as a critical mediator of vascular remodeling by regulating pericyte function and endothelial basement membrane formation during angiogenesis (43). In the tumor microenvironment, CTGF and the CXCR2 chemokine ligand axis have also been implicated as promoters of tumor angiogenesis in a variety of PDA models (42,44). In contrast to the prior finding that inhibition of CXCR2 resulted in reduced CTGF levels and regulated blood vessel density and tumor growth in the related Ptf1a cre/+ ;LSL-Kras G12D/+ ;Tgfbr2 flox/flox mouse model (44), FG-3019 had no effect on mean vessel density over the time course of treatment in KPC mice, and suggests that the relevant therapeutic targets here are neoplastic cell-intrinsic.…”

miR141–CXCL1–CXCR2 Signaling–Induced Treg Recruitment Regulates Metastases and Survival of Non–Small Cell Lung Cancer

“…CXCR2 deficiency could inhibit inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation (36). CXCR2 has been proved to be a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues in both tumor initiation stage and tumor promotion stage (37). Therefore, CXCR2 receptor antagonists are a potential pharmacologic approach in cancer and chronic inflammatory diseases (38,39).…”

Therapeutic effect of c‐Jun N‐terminal kinase inhibition on pancreatic cancer

“…(19) Because the clinical and histopathological manifestations of Kras G12D +Tgfbr2 KO mice recapitulate human PDAC, these mice are considered a good model of human PDAC and are used for the evaluation of candidate treatment drugs for PDAC. (20) In the present study, we examined the role of JNK and the effect of JNK inhibition in pancreatic cancer using pancreatic cancer cell lines and Kras G12D +Tgfbr2 KO mice. We found that inhibition of JNK can be a potential therapy for pancreatic cancer.…”