Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma

Abstract

Background Cancer‐associated fibroblasts (CAFs) are among the most prominent cells during the desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC). However, CAFs are heterogeneous and the precise origins are not fully elucidated. This study aimed to explore whether monocytes can transdifferentiate into fibroblasts in PDAC and evaluate the clinical significance of this event. Methods CD14 + monocytes were freshly isolated from human peripheral blood. Immunofluorescence, reverse transcription‐quantitative PCR, western blot, flow cytometry and enzyme‐linked immunosorbent assay were used to detect the expression of αSMA, fibronectin, and other relevant molecules. In addition, latex beads with a mean particle size of 2.0 µm were used to assess the phagocytic capacity. Moreover, RNA sequencing (RNA‐seq) was performed to identify the differences induced by H 2 O 2 and the underlying mechanisms. Results Immunofluorescence identified αSMA and fibroblast‐specific protein 1 expression by tumor‐associated macrophages in PDAC. The in vitro experiment revealed that oxidative stress (H 2 O 2 or radiation) induced monocyte‐to‐myofibroblast transdifferentiation (MMT), as identified by upregulated αSMA expression at both the RNA and protein levels. In addition, compared with freshly isolated monocytes, human monocyte‐derived macrophages increased fibronectin expression. RNA‐seq analysis identified p53 activation and other signatures accompanying this transdifferentiation; however, the p53 stabilizer nutlin‐3 induced αSMA expression through reactive oxygen species generation but not through the p53 transcription/mitochondria‐dependent pathway, whereas the p38 inhibitor SB203580 could partially inhibit αSMA expression. Finally, MMT produced a unique subset of CAFs with reduced phagocytic capacity that could promote the proliferation of pancreatic cancer cells. Conclusions Oxidative stress in the tumor microenvironment could induce MMT in PDAC, thus inducing reactive stroma, modulating immunosuppression, and promoting tumor progression. Reducing oxidative stress may be a promising future therapeutic regimen.

Monocyte and macrophage derived myofibroblasts: Is it fate? A review of the current evidence

“…Pancreatic ductal adenocarcinoma (PDAC) is characterised by a fibrotic response that involves cancer-associated fibroblasts, tumourassociated macrophages, and ECM. 41 Cancer-associated fibroblasts are believed to play a role in cancer initiation and progression. 41 These cells may also secrete ECM and chemokines, leading to chemoresistance and hindrance of the delivery of therapeutics.…”

“…41 Cancer-associated fibroblasts are believed to play a role in cancer initiation and progression. 41 These cells may also secrete ECM and chemokines, leading to chemoresistance and hindrance of the delivery of therapeutics. 41…”

The use of an oxidative stress scoring system in prognostic prediction for kidney renal clear cell carcinoma

“…The use of an oxidative stress scoring system in prognostic prediction for kidney renal clear cell carcinoma Dear editor, Oxidative stress induced by reactive oxygen species (ROS) production plays a key role in tumor initiation and progression [1,2]. Emerging evidence has shown that oxidative stress-related genes could be used as biomarkers for predicting the progression and prognosis of malignant tumors [3].…”

Cellular Heterogeneity of Pancreatic Stellate Cells, Mesenchymal Stem Cells, and Cancer-Associated Fibroblasts in Pancreatic Cancer

“…Resident fibroblasts and especially PSCs are major sources of CAFs in pancreatic cancer [ 21 , 22 , 23 ]. Furthermore, adipocytes, pericytes, monocytes, endothelial cells, and bone marrow-derived or adipose-derived mesenchymal stem cells (MSCs) can differentiate into CAFs ( Figure 1 ) [ 24 , 25 , 26 , 27 ]. Cultured MSCs themselves exhibit a high cellular plasticity and capacity to undergo osteogenic, adipogenic, myogenic, and chondrogenic differentiation [ 28 ].…”