Abstract
BackgroundTumor-stroma reaction is associated with activation of fibroblasts. Nemosis is a novel type of fibroblast activation. It leads to an increased production of growth factors and proinflammatory and proteolytic proteins, while at the same time cytoskeletal proteins are degraded. Here we used paired normal skin fibroblasts and cancer-associated fibroblasts (CAF) and primary and recurrent oral squamous cell carcinoma (SCC) cells to study the nemosis response.Principal FindingsFibroblast nemosis was analyzed by protein and gene expression and the paracrine regulation with colony formation assay. One of the normal fibroblast strains, FB-43, upregulated COX-2 in nemosis, but FB-74 cells did not. In contrast, CAF-74 spheroids expressed COX-2 but CAF-43 cells did not. Alpha-SMA protein was expressed in both CAF strains and in FB-74 cells, but not in FB-43 fibroblasts. Its mRNA levels were downregulated in nemosis, but the CAFs started to regain the expression. FSP1 mRNA was downregulated in normal fibroblasts and CAF-74 cells, but not in CAF-43 fibroblasts. Serine protease FAP was upregulated in all fibroblasts, more so in nemotic CAFs. VEGF, HGF/SF and FGF7 mRNA levels were upregulated to variable degree in nemosis. CAFs increased the colony formation of primary tumor cell lines UT-SCC-43A and UT-SCC-74A, but normal fibroblasts inhibited the anchorage-independent growth of recurrent UT-SCC-43B and UT-SCC-74B cells.ConclusionsNemosis response, as observed by COX-2 and growth factor induction, and expression of CAF markers α-SMA, FSP1 and FAP, varies between fibroblast populations. The expression of CAF markers differs between normal fibroblasts and CAFs in nemosis. These results emphasize the heterogeneity of fibroblasts and the evolving tumor-promoting properties of CAFs.
Highlights
Tumor microenvironment plays a major role in cancer progression and fibroblasts are known to be key components of the tumor stroma
The expression of cancer-associated fibroblasts (CAF) markers differs between normal fibroblasts and CAFs in nemosis
Among the activated fibroblasts are cancer-associated fibroblasts (CAF), that are characterized by increased mitotic index, mutations in tumor suppressor genes such as p53 and by increased secretion of growth factors, chemokines and components of extracellular matrix (ECM) [2,3], changes which all are involved in invasion and tumor growth [4].Widely used CAF markers include a-smooth muscle actin (a-SMA), fibroblast specific protein 1 (FSP1, known as S100A4) and fibroblast activation protein (FAP, known as seprase) [5]. a-SMA, a component of the cytoskeleton, is the most often used marker for activated fibroblasts
Summary
Tumor microenvironment plays a major role in cancer progression and fibroblasts are known to be key components of the tumor stroma. The dependence of carcinomas on stromal fibroblasts decreases as the cancer progresses, partly through a switch in epithelial cells from paracrine to autocrine regulation [1,2]. A-SMA, a component of the cytoskeleton, is the most often used marker for activated fibroblasts. FSP1 belongs to the S100 superfamily of calcium-binding proteins It promotes tumor growth by regulating cell cycle progression and cytoskeletal integrity [7]. Nemosis is a novel type of fibroblast activation It leads to an increased production of growth factors and proinflammatory and proteolytic proteins, while at the same time cytoskeletal proteins are degraded. We used paired normal skin fibroblasts and cancer-associated fibroblasts (CAF) and primary and recurrent oral squamous cell carcinoma (SCC) cells to study the nemosis response
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