Nab‐paclitaxel interrupts cancer‐stromal interaction through C‐X‐C motif chemokine 10‐mediated interleukin‐6 downregulation in vitro

Abstract

Cancer‐associated fibroblasts (CAF), derived from stroma of cancer tissues, interact with cancer cells and play an important role in cancer initiation, growth, and metastasis. Nab‐paclitaxel (nab‐PTX) is a 130 nm albumin‐binding paclitaxel and recommended for many types of cancer chemotherapy. The nab‐PTX stromal‐disrupting effect during pancreatic cancer treatment has been reported. The aim of the present study was to determine the role of nab‐PTX in cancer cells and CAF interaction. Cancer cells (MIA PaCa‐2 and Panc‐1) were cocultured with CAF or treated with CAF conditioned medium, after which their migration and invasion ability, epithelial‐mesenchymal transition (EMT)‐related marker expression and C‐X‐C motif chemokine 10 (CXCL10) expression and secretion were detected. Nab‐PTX treatment was carried out during the coculture system or during preparation of CAF conditioned medium. Then cancer cell migration and invasion ability, EMT‐related marker expression, CXCL10 expression and secretion, and interleukin‐6 (IL‐6) expression and secretion by CAF were checked After coculture with CAF, migration and invasion ability of cancer cells increased. CAF also downregulated E‐cadherin and upregulated N‐cadherin and vimentin expression in cancer cells. During coculture or stimulation with cancer cell‐cultured medium, CAF significantly increased IL‐6 expression and secretion. However, nab‐PTX in the coculture system canceled CAF‐induced migration and invasion promotion and EMT‐related gene changes. Moreover, nab‐PTX increased CXCL10 expression of cancer cells which blocked CAF IL‐6 expression and secretion. Nab‐PTX treatment could increase CXCL10 expression of cancer cells which blocks CAF cancer cell migration and invasion‐promoting effect by inhibiting IL‐6 expression.

Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity

“…The pathways that activate CAFs are Sonic Hedgehog, TGFβ, TNFα, IL-1, IL-6, and IL-10. CAFs produce most of the extracellular matrix, highly abundant in PDAC, but they also favor tumor growth and metastases by secreting inflammatory cytokines, mainly IL-6; chemokines; and chemokines ligands, namely CCL2 and C–X–C motif chemokine ligand 12 (CXCL12) [63,73,74,75].…”

“…A typical proinflammatory cytokine, IL-6, also has a pro-tumorigenic effect [70,62]. In vitro studies have shown that both pancreatic cancer cell lines and CAFs produce IL-6, which might act as an autocrine and paracrine stimulus causing increased tumor cell migration and invasion, as well as epithelial to mesenchymal transition (EMT) [60,63]. In PDAC patients, the elevated IL-6 levels found in serum, pancreatic juice and tissue, appear to predict tumor stage and survival, thus supporting the potential role of this cytokine as a malignancy predictor, but its sensitivity and specificity are extremely variable [59].…”

Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

“…For example, Phase II clinical trials (NCT01821729, NCT03563248) in pancreatic cancer using a combination of losartan and FOLFIRINOX recently showed extended patient prognosis and was associated with negative resection margin for 61% of patients [ 189 ]. The administration of nab-paclitaxel (abraxane) combined with gemcitabine decreases the production of type-I collagen and the secretion of CXCL10 and IL-6 in co-cultures of pancreatic cells and CAFs [ 190 , 191 ]. A recent Phase III clinical trial tested nab-paclitaxel in combination with atezolizumab, a monoclonal antibody against PD-L1, in unresectable and metastatic triple-negative breast cancer (NCT02425891) and metastatic lung cancer (NCT02367781), showing an increase in PFS and OS [ 192 , 193 , 194 ].…”

The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma

“…We have previously reported the role of the transcriptional factor NF-E2-related factor 2 (Nrf2) in cancer-TAM interactions in hepatocellular carcinoma (HCC) and pancreatic cancer [ 15 ] and cancer-CAF interactions through IL-6 and CXCL10 in pancreatic cancer [ 16 ]. Considering our results and previous findings, CAFs and TAMs play a central role in the development of the TME, and the establishment of cancer-CAF-TAM interactions likely increase the malignancy of tumors.…”