Collective migration of cancer‐associated fibroblasts is enhanced by overexpression of tight junction‐associated proteins claudin‐11 and occludin

Abstract

It has been suggested that cancer-associated fibroblasts (CAFs) positioned at the desmoplastic areas of various types of cancer are capable of executing a migratory program, characterized by accelerated motility and collective configuration. Since CAFs are reprogrammed derivatives of normal progenitors, including quiescent fibroblasts, we hypothesized that such migratory program could be context-dependent, thus being regulated by specific paracrine signals from the adjacent cancer population. Using the traditional scratch assay setup, we showed that only specific colon cancer cell lines (i.e. HT29) were able to induce collective CAF migration. By performing quantitative proteomics (SILAC), we identified a 2.7-fold increase of claudin-11, a member of the tight junction apparatus, in CAFs that exerted such collectivity in their migratory pattern. Further proteomic investigations of cancer cell line secretomes revealed a specific signature, involving TGF-β, as potential mediator of this effect. Normal colonic fibroblasts stimulated with TGF-β exerted myofibroblastic differentiation, occludin (OCLN) and claudin-11 (CLDN11) overexpression and cohort formation. Subsequently, inhibition of TGF-β attenuated all the previous effects. Immunohistochemistry of the universal tight junction marker occludin in a cohort of 30 colorectal adenocarcinoma patients defined a CAF subpopulation expressing tight junctions. Overall, these data suggest that cancer cells may induce CLDN11 overexpression and subsequent collective migration of peritumoral CAFs via TGF-β secretion.

Low‐quality rice straw forage increases the permeability of mammary epithelial tight junctions in lactating dairy cows

“…The OCLN, ZO-1, CLDN1, CLDN3, and CLDN4 are the main tight-junction proteins in the mammary gland. [25][26][27] In the current study, mammary expression of these proteins, except OCLN, showed no difference in the cows fed two diets. Occludin plays an important role in forming the tight junction paracellular permeability barrier.…”

“…The OCLN, ZO‐1, CLDN1, CLDN3, and CLDN4 are the main tight‐junction proteins in the mammary gland . In the current study, mammary expression of these proteins, except OCLN, showed no difference in the cows fed two diets.…”

“…In the current study, mammary expression of these proteins, except OCLN, showed no difference in the cows fed two diets. Occludin plays an important role in forming the tight junction paracellular permeability barrier . The increased permeability of tight junctions might thus partially result from changes in the expression of OCLN in RS‐fed cows, compared with that of AH‐fed animals.…”

“…Occludin plays an important role in forming the tight junction paracellular permeability barrier. 25 The increased permeability of tight junctions might thus partially result from changes in the expression of OCLN in RS-fed cows, compared with that of AH-fed animals. Another possibility of causing higher permeability of the tight junction might be the changes of apoptosis/proliferation status in mammary epithelial cells.…”

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

“…There was a substantial increase in expression of CAF markers ACTA2, FAP, and S100A4 RNA and α-SMA protein (Supplemental Figure 2, D and E; see complete unedited blots in the supplemental material). Two characteristics of transformed fibroblasts in vitro are increased production of proinflammatory cytokines and increased migration (13,27). Conditioned medium from NE-treated cancer cells increased migratory potential (Supplemental Figure 2F) and expression of proinflammatory cytokines such as MCP1, CXCL1, MIF, GM-CSF, and G-CSF (Supplemental Figure 2G) in NOF151 cells.…”