Cancer Associated Fibroblasts and Senescent Thyroid Cells in the Invasive Front of Thyroid Carcinoma

Abstract

Thyroid carcinoma (TC) comprises several histotypes with different aggressiveness, from well (papillary carcinoma, PTC) to less differentiated forms (poorly differentiated and anaplastic thyroid carcinoma, PDTC and ATC, respectively). Previous reports have suggested a functional role for cancer-associated fibroblasts (CAFs) or senescent TC cells in the progression of PTC. In this study, we investigated the presence of CAFs and senescent cells in proprietary human TCs including PTC, PDTC, and ATC. Screening for the driving lesions BRAFV600E and N/H/KRAS mutations, and gene fusions was also performed to correlate results with tumor genotype. In samples with unidentified drivers, transcriptomic profiles were used to establish a BRAF- or RAS-like molecular subtype based on a gene signature derived from The Cancer Genome Atlas. By using immunohistochemistry, we found co-occurrence of stromal CAFs and senescent TC cells at the tumor invasive front, where deposition of collagen (COL1A1) and expression of lysyl oxidase (LOX) enzyme were also detected, in association with features of local invasion. Concurrent high expression of CAFs and of the senescent TC cells markers, COL1A1 and LOX was confirmed in different TC histotypes in proprietary and public gene sets derived from Gene Expression Omnibus (GEO) repository, and especially in BRAF mutated or BRAF-like tumors. In this study, we show that CAFs and senescent TC cells co-occur in various histotypes of BRAF-driven thyroid tumors and localize at the tumor invasive front.

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…Physiologically, natural gastric stroma contains only a few fibroblasts, and those are mainly myofibroblasts. The number of fibroblasts is significantly increased in tissues affected by inflammation or neoplasm [228][229][230][231]. In a gastric cancer microenvironment, macrophages via interaction with mesenchymal stem cells induce differentiation of cancer-associated fibroblasts (CAFs) [232][233][234].…”

The Role of Exosomes in Thyroid Cancer and Their Potential Clinical Application

“…Exosomes released from CAFs contribute to tumor progression and metastasis by transferring substances to cancer cells, and exosomes secreted by cancer cells can promote CAF transformation (20,80). The crosstalk between TC cells and CAFs has been continuously revealed, and the role of exosomes in their interactions is worthy of further investigation (81). The ongoing revelation of the underlying mechanisms and pathogenesis of TC progression, as well as the influence of exosomes on these mechanisms, may provide more strategies for eventually curing TC.…”

Tumor Cells and Cancer-Associated Fibroblasts: A Synergistic Crosstalk to Promote Thyroid Cancer

“…Higher levels of α-SMA-positive areas were found preferentially localized at the tumor invasive front, in PTC and ATC. However, these studies did not find a specific or clear association between CAFs and a particular type of thyroid carcinoma [ 35 ]. Conversely, a very rare or absent infiltration of CAFs was described by α-SMA immunostaining in a study performed on patients with ATC [ 36 ].…”

“…Twenty-eight different collagens have been identified [ 42 ], and their assembly is highly regulated by the activity of enzymes, such as lysyl oxidase (LOX) [ 43 ]. Interestingly, LOX, an enzyme responsible for collagen cross-linking, was found to be highly expressed in aggressive thyroid carcinomas as compared to DTCs and normal thyroid tissues [ 35 , 44 ]. In addition, LOX inhibition significantly reduced the migration and invasion of ATC cell lines [ 44 ].…”