Cancer‐associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness: Potential role of ADAM9

Abstract

The tumor microenvironment plays a key role in cancer aggressiveness.Desmoplastic reaction (DR), morphologically classified as Mature, Intermediate and Immature types, has previously been shown to be highly prognostic in colorectal cancer (CRC) and it consists to a large extent of cancer-associated fibroblasts (CAFs). The aim of our study was to characterize the molecular background of DR and understand the effects of CAFs in tumor aggressiveness. The prognostic significance of DR was initially examined in 1497 patients. Then CAFs originating from patient tissues with different DR types were isolated and their impact on tumor growth was examined both in vitro and in vivo. DR was shown to be highly prognostic, with patients within the Immature DR group conferring the worst relapse-free survival. The conditioned media of CAFs from tumor with Immaturetype DR (CAFs Immature ) significantly increased proliferation and migration of CRC cell lines and growth of CRC-derived organoids compared to that of CAFs from Mature-type DR (CAFs Mature ). Subcutaneous or orthotopic implantation of CRC cells together with CAFs Immature in mice significantly promoted tumor growth and dissemination compared to implantation with CAFs Mature . Systematic examination of the expression of "a disintegrin and metalloproteinases" (ADAMs) in CAFs isolated from CRC tissues showed that the secreted isoform of ADAM9 (ADAM9s) was significantly higher in CAFs Immature than in CAFs Mature . Knockdown of ADAM9s in CAFs Immature abrogated the promoting effects on CRC cell proliferation and migration. CAFs-derived ADAM9s is implicated in deteriorating survival in CRC patients with Immature-type DR by increasing tumor cell proliferation and dissemination.

CAF signature predicts the prognosis of colorectal cancer patients: A retrospective study based on bulk RNA sequencing and single-cell RNA sequencing data

“…[18,19] For example, CAFs secrete ADAM9 to stimulate the growth and migration of human CRC cells. [20] Our study, based on bulk RNA sequencing and scRNA sequencing data, validated that more CAFs were enriched in the tumor microenvironment compared to the adjacent normal microenvironment. Besides, in line with the previous finding, [10] we uncovered that there were 3 subtypes of CAFs in CRC tissues.…”

Desmoplastic Reaction Associates with Prognosis and Adjuvant Chemotherapy Response in Colorectal Cancer: A Multicenter Retrospective Study

“…Ao and colleagues demonstrated that CAFs derived from colorectal cancer tissue with immature-type DR overexpressed ADAM9s and stimulated cell proliferation and migration of colorectal cancer cell lines in vitro . In this regard, they supposed ADAM9-targeting antibody–drug conjugates may be a good drug candidate ( 29 ). However, predictive value of DR on ACT has been rarely reported in previous studies.…”

Reciprocal Regulation of Cancer-Associated Fibroblasts and Tumor Microenvironment in Gastrointestinal Cancer: Implications for Cancer Dormancy

“…This leads to ECM stiffness and further feedback to TGF-β induction and contributes to a tumor-promoting inflammatory environment [33,34]. CAFs also secrete a disintegrin and metalloproteinase 9 (ADAM9), which has been implicated in increasing the proliferation and dissemination of CRC cells [35]. Recent literature suggests that ADAMs are considered biochemical markers of GI tumorigenesis due to their protein hydrolysis and adhesion activities [36,37].…”