CCL26 is upregulated by nab-paclitaxel in pancreatic cancer–associated fibroblasts and promotes PDAC invasiveness through activation of the PI3K/AKT/mTOR pathway

Abstract

Abstract Recently, the combined use of FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine plus nab-paclitaxel has significantly improved the prognosis of patients with pancreatic cancer. However, there is still a high proportion of patients who develop metastatic pancreatic cancer in the course of chemotherapy or within a short period after chemotherapy. Previous reports have shown that chemotherapy-driven cytokine storms or the direct effects of certain chemotherapeutics on stromal and/or immune cells collectively change the microenvironment of the primary tumor, thus indirectly promoting metastasis. However, the mechanism underlying chemotherapy-induced metastasis in the course of chemotherapy, and afterwards, remains elusive in pancreatic cancer. In the present study, we aimed to determine the expression of CCL26 in the pancreatic cancer–associated fibroblasts (CAFs) after nab-paclitaxel treatment and to explore the role of CCL26 in the pancreatic adenocarcinoma (PDAC) invasion. Our results showed that nab-paclitaxel increased CCL26 mRNA and protein expression levels in a dose- and time-dependent manner. Subsequently, PDAC cell lines were treated with recombinant CCL26 for 48 h. The transwell migration assay showed that recombinant CCL26 enhanced the invasion of PDAC cells. Western blot analysis showed that the protein expression levels of phospho-(p-)PI3K, p-AKT, and p-mTOR were increased by CCL26 in PDAC cells. CCL26 expressions in 95 PDAC tissues and adjacent normal tissues were evaluated using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. CCL26 was found to be overexpressed in PDAC samples, and upregulated CCL26 expression was significantly associated with advanced perineural invasion, lymph node metastasis, and poor differentiation. In summary, our results showed that nab-paclitaxel increased the expression of CCL26 in CAFs, and CCL26 enhanced the invasive potential of pancreatic cancer cells by activating the PI3K/AKT/mTOR axis. Thus, CCL26 may be a potential prognostic biomarker for pancreatic cancer.