Interleukin 33/ST2 Axis Components Are Associated to Desmoplasia, a Metastasis-Related Factor in Colorectal Cancer

Abstract

In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) are the most abundant component from the tumor microenvironment (TM). CAFs facilitate tumor progression by inducing angiogenesis, immune suppression and invasion, thus altering the organization/composition of the extracellular matrix (i.e., desmoplasia) and/or activating epithelial-mesenchymal transition (EMT). Soluble factors from the TM can also contribute to cell invasion through secretion of cytokines and recently, IL-33/ST2 pathway has gained huge interest as a protumor alarmin, promoting progression to metastasis by inducing changes in TM. Hence, we analyzed IL-33 and ST2 content in tumor and healthy tissue lysates and plasma from CRC patients. Tissue localization and distribution of these molecules was evaluated by immunohistochemistry (using localization reference markers α-smooth muscle actin or α-SMA and E-cadherin), and clinical/histopathological information was obtained from CRC patients. In vitro experiments were conducted in primary cultures of CAFs and normal fibroblasts (NFs) isolated from tumor and healthy tissue taken from CRC patients. Additionally, migration and proliferation analysis were performed in HT29 and HCT116 cell lines. It was found that IL-33 content increases in left-sided CRC patients with lymphatic metastasis, with localization in tumor epithelia associated with abundant desmoplasia. Although ST2 content showed similarities between tumor and healthy tissue, a decreased immunoreactivity was observed in left-sided tumor stroma, associated to metastasis related factors (advanced stages, abundant desmoplasia, and presence of tumor budding). A principal component analysis (including stromal and epithelial IL-33/ST2 and α-SMA immunoreactivity with extent of desmoplasia) allowed us to distinguish clusters of low, intermediate and abundant desmoplasia, with potential to develop a diagnostic signature with benefits for further therapeutic targets. IL-33 transcript levels from CAFs directly correlated with CRC cell line migration induced by CAFs conditioned media, with rhIL-33 inducing a mesenchymal phenotype in HT29 cells. These results indicate a role of IL-33/ST2 in tumor microenvironment, specifically in the interaction between CAFs and epithelial tumor cells, thus contributing to invasion and metastasis in left-sided CRC, most likely by activating desmoplasia.

Cancer associated-fibroblast-derived exosomes in cancer progression

“…CAFs can not only serve as physical barriers to protect the cancer cells from the external drugs and the attack of immune cells, but also secrete abundant soluble factors, EVs and ECM to regulate other cells type in TME, which include stimulating cancer cell proliferation, invasion and migration, angiogenesis and therapy resistance. Moreover, CAFs can regulate cancer cell metabolism and stimulate immune evasion of cancer cells factor 1 (SDF1), C-X-C motif chemokine ligand 8 (CXCL8) and cyclooxygenase-2 (COX-2) [15,[57][58][59][60][61], and different molecules mediate diverse effects. For example, secretion of TGF-β by CAFs promotes the EMT of breast cancer cells via TGF-β/SMAD and non-SMAD signaling pathways [62,63], and facilitates the tumor growth and metastasis in colorectal cancer [64,65].…”

Downregulated miR-524-5p Participates in the Tumor Microenvironment of Ameloblastoma by Targeting the Interleukin-33 (IL-33)/Suppression of Tumorigenicity 2 (ST2) Axis

“…IL-33 mainly participates in the induction of type 2 immune responses through its receptor, ST2 [25]. IL-33/ST2 contributes to breast cancer [26], colorectal cancer [27], and gastric cancer [28]. However, the role of IL-33/ST2 has been not reported in AB and its underlying mechanism remains unclear.…”

Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance

“…These factors are prostaglandins, cytokines, and other paracrine factors, which have distinctive modes of action. Prostaglandins and cytokines act especially as immunomodulators, by promoting or inhibiting the progression of CRC[ 1 , 32 , 33 ]. Growth factors such as TGF-β, vascular endothelial growth factor (VEGF), and EGF promote the transformation and development of neoplastic cells by inducing proliferation, invasion, and migration responses and also by affecting the TME[ 21 ].…”