Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with high morbidity and mortality worldwide. To date, limited therapeutic achievements targeting cell proliferation and related mechanisms has led researchers to focus on the microenvironment where pancreatic cancers develop. The anomalous proliferation of stromal cells, such as pancreatic stellate cells, and an increased deposition of altered matrix proteins create an environment that facilitates tumor growth, metastasis and drug resistance. Here, we summarize our understanding of recent advances in research about the role of fibrosis in pancreatic cancer progression, with particular emphasize on the involvement of fibrotic machineries such as wound healing, extra cellular matrix degradation, and epithelial-to-mesenchymal transition. The precise influence of these mechanisms on the biological behaviors and growth of cancer cells has great impact on clinical therapy and therefore deserves more attention. We also discuss the role of various stromal components in conferring drug resistance to PDAC which further worsening the pessimistic disease prognosis. A more in depth understanding of cancer-stroma crosstalk within the tumor microenvironment and stroma based clinical and translational therapies may provide new therapeutic strategies for the prevention of pancreatic cancer progression.

Prognostic significance of stem cell/ epithelial-mesenchymal transition markers in periampullary/pancreatic cancers: FGFR1 is a promising prognostic marker

“…Although this finding seems conflicting with the first finding, high FGFR1 expression is correlated with the degree of fibrosis but is not strictly linked together. In pancreatic cancer, pancreatic stellate cells (PSCs) in the stroma are considered as the sprouting seeds of cancer progression and metastasis [20]. These are essential components of the tumor-stromal organization and are usually present as quiescent or inactive cells in normal pancreatic tissue.…”

“…These are essential components of the tumor-stromal organization and are usually present as quiescent or inactive cells in normal pancreatic tissue. These cells are believed to play a key role in extracellular matrix production and regulate or promote EMT [2,20]. It is possible that after surgery, tumors with a higher degree of fibrosis might have increased remnant fibrotic tissue containing activated PSCs, and this could be the foci of recurrence.…”

Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer

“…This suggests that serum PRO‐C3 may serve as prognostic marker in patients with PC. In support of this hypothesis, collagen turnover rate needs to be maintained in normal tissue homeostasis, and changes in the deposition of collagens result in the tissue fibrosis that drives tumorigenesis . Hence type III collagen synthesis may be a major component of the dense stroma (desmoplastic reaction) in the tumor and linked to tumor growth, metastasis and drug resistance.…”

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…BTK inhibitors also produce an unexpected anti-fibrotic effect (202). PDAC cancers are rich in stromal cells and fibro-inflammatory reactions, which support chemotherapy resistance (203). A phase 3 clinical trial of ibrutinib in combination with chemotherapy in PDAC was recently completed (April 2019; NCT02436668) (204).…”