Journal
CANCER LETTERS
Volume 528, Issue -, Pages 59-75Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.12.025
Keywords
Cancer-associated fibroblasts; Thrombospondin 2; Tumor-stromal cell communication; Integrin alpha(v)beta(3)/CD36-MAPK cascade; Tumor progression
Categories
Funding
- National Key R D Program [2018YFC1313101, 2017ZX10203205-003-001, 2016YFC0901403]
- National Natural Science Foundation of China [81872033, 82073327]
- CIFMS [2021-I2M-1-066]
Ask authors/readers for more resources
The cancer-associated fibroblasts (CAFs) and thrombospondin 2 (THBS2) in the microenvironment of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor development and prognosis. It has been found that elevated THBS2 expression in PDAC is mainly located in the stroma and is associated with tumor progression and poor prognosis. The study also revealed that cancer cell-secreted TGF-beta 1 activates CAFs to induce THBS2 expression, which then promotes tumor growth and adhesion in PDAC cells.
The pancreatic ductal adenocarcinoma (PDAC) microenvironment contains dense desmoplastic stroma dominated by cancer-associated fibroblasts (CAFs) and is crucial to cancer development and progression. Several studies have revealed that thrombospondin 2 (THBS2) is a valuable serological-marker in PDAC. However, the detailed mechanism of the cancer-stroma interactome remains unclear. Here we showed that elevated THBS2 expression in PDAC was predominantly restricted to stroma and correlated with tumor progression and poor prognosis by quantitative proteomics and immunohistochemistry analyses. RNA in situ hybridization confirmed that CAFs but not neoplastic cells expressed THBS2 in precancerous lesions and its levels gradually increased with disease progression in genetically engineered mouse models. Mechanistically, cancer cell-secreted TGF-beta 1 activated CAFs to induce THBS2 expression via the p-Smad2/3 pathway. Consequently, CAF-derived THBS2 bound to the membrane receptors integrin alpha(v)beta(3)/CD36 and activated the MAPK pathway in PDAC cells to promote tumor growth and adhesion in vitro and in vivo. Inhibition of integrin alpha(v)beta(3), CD36, MEK and JNK rescued THBS2-induced malignant phenotypes. In conclusion, the TGF-beta 1-THBS2-integrin alpha(v)beta(3)/CD36-MAPK cascade forms a complex feedback circuit to mediate reciprocal interactions of pancreatic cancer cells-CAFs. THBS2 may act as a novel therapeutic-target to block the cancer-stroma communication.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available