CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer

Abstract

Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the effect on tumor invasion and angiogenesis were evaluated with or without a conditioned medium from the mast cell line HMC-1 (human mast cell line-1 cells) and CAFs. Beside the clinical outcome of a homogenous population of PDAC patients, receiving GEM/NAB, was correlated to the circulating levels of mast cell tryptase and to a panel of inflammatory and immunosuppressive cytokines. CAFs neither affected drugs’ cytotoxicity nor the inhibition of angiogenesis, but promoted tumor cell invasion. The MC instead, caused resistance to drugs by reducing apoptosis, by activating the TGF-β signalling and by promoting tumor invasion. Indeed, the inhibition of TβRI serine/threonine kinase activity by galunisertib restored drugs cytotoxicity. Moreover, MC induced the release of TGF-β1, and increased expression of PAR-2, ERK1/2 and Akt activation. Accordingly, TGF-β1, tryptase and other pro-inflammatory and immunosuppressive cytokines increased in the unresponsive patients. In conclusion, MC play a pivotal role in the resistance to GEM/NAB. A correlation between high level of circulating pro-inflammatory/ immunosuppressive cytokines and unresponsiveness was found in PDAC patients.

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

“…Pancreatic cancer (PC) is one of the most lethal human cancers, but presently, both standard chemotherapy regimens and targeted agents provide unsatisfactory responses in terms of survival for patients with advanced PC [33]. This issue may be partly explained by a complex cross-talk between PC cells and microenvironment components, such as stromal and immune cells, as well as soluble proteins, including growth factors and cytokines, which play a crucial role in conferring chemoresistance, promoting tumor growth, metastatic dissemination and epithelial-mesenchymal transition (EMT), supporting immunoescape and interfering with drug delivery [34][35][36]. Thus, more effective therapeutic strategies and agents are needed to improve pancreatic cancer treatment.…”

“…According to the role of microtubules in motility [31], parbendazole also hampered AsPC-1 and Capan-2 cell migration. In this regard, considering the important role of microtubules in cells of tumor microenvironment and their implication in survival, drug resistance and invasion in pancreatic and other tumors [34][35][36]41,42], it is possible that parbendazole may affect also the tumor milieu. Notably, several studies indicated that the PC aggressive phenotype could associate to WNT/β-catenin pathway activation, which plays a pivotal role both in invasive and in immunotolerant behavior of PC [43][44][45].…”

Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen

“…The mechanisms of CAF-mediated therapeutic resistance include HGF/MET by restoring survival signaling pathway (PI3K or MAPK), PDGF/PDGF-R by improving IFP, IL-6 by activating of STAT3, SDF-1/CXCR4 by BCL-2 / BCL-XL or activating NOTCH pathway to regulate CSCs and AnXA1/TGR-beta/CA IX/ MMP-2/MMP-9 to regulate EMT [40]. Indeed, it has been shown that CAFs and TGF-β signaling activation contribute to chemotherapy resistance in cancer [41]. Another study showed that HCC patients receiving sorafenib may benefit from immune modulation strategies [42].…”

Bone metastasis as primary presentation of pancreatic ductal adenocarcinoma: A case report and literature review

“…12 As in other several solid and hematologic cancer, [13][14][15] the tumor microenvironment emerged as a pivotal driver of metastatic niche 16 being correlated at the same time to cell-adhesion dependent and independent drug-resistance development. [17][18][19][20] Thus, several approaches have been envisioned in order to molecularly overcome this malignant phenotype, in order to target both the cancer cells and the tumoral milieu. [21][22][23] Variable incidence of bone metastases from PDAC reported in literature (from 5% to 20%) should be conditioned by either the possible overlapping between symptoms related to the primary tumor and bone localization or the longer survival obtained in the last few years due the availability of new and more active chemotherapy regimens in both adjuvant and advanced settings.…”