Fibronectin extra domain A (EDA) sustains CD133+/CD44+ subpopulation of colorectal cancer cells

Abstract

Fibronectin is a major extracellular matrix glycoprotein with several alternatively spliced variants, including extra domain A (EDA), which was demonstrated to promote tumorigenesis via stimulating angiogenesis and lymphangiogenesis. Given that CD133+/CD44+ cancer cells are critical in tumorigenesis of colorectal cancer (CRC), we hypothesize that fibronectin EDA may promote tumorigenesis by sustaining the properties of CD133+/CD44+ colon cancer cells. We found that tumor tissue and serum EDA levels are substantially higher in advanced versus early stage human CRC. Additionally we showed that tumor tissue EDA levels are positively correlated with differentiation status and chemoresistance, and correlated with a poor prognosis of CRC patients. We also showed that in colon cancer cells SW480, CD133+/CD44+ versus CD133−/CD44− cells express significantly elevated EDA receptor integrin α9β1. Silencing EDA in SW480 cells reduces spheroid formation and cells positive for CD133 or CD44, which is associated with reduced expressions of embryonic stem cell markers and increased expressions of differentiation markers. Blocking integrin α9β1 function strongly reversed the effect of EDA overexpression. We also provided evidence suggesting that EDA sustains Wnt/β-catenin signaling activity via activating integrin/FAK/ERK pathway. In xenograft models, EDA-silenced SW480 cells exhibit reduced tumorigenic and metastatic capacity. In conclusions, EDA is essential for the maintenance of the properties of CD133+/CD44+ colon cancer cells.

Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

“…Fibronectin and Lgr5 mRNA expression were both down-regulated upon treatment with Sal in SW620 and HT29 cells. The importance of Fibronectin and its spliced variant extra domain A (EDA) has been characterized as essential for the phenotype and the tumorigenic properties of CD133 + /CD44 + CRC cells [40]. Furthermore, a correlation between Fibronectin EDA-level and stage of disease and chemoresistance of CRC patients was reported [40].…”

“…The importance of Fibronectin and its spliced variant extra domain A (EDA) has been characterized as essential for the phenotype and the tumorigenic properties of CD133 + /CD44 + CRC cells [40]. Furthermore, a correlation between Fibronectin EDA-level and stage of disease and chemoresistance of CRC patients was reported [40]. Given that silencing of EDA resulted in downregulation of Wnt/β-catenin signaling and the inhibitory effects of Sal on Fibronectin expression in our study, Sal might be regarded as an inhibitor of the regulatory Fibronectin/Wnt/β-catenin signaling loop in human CRC cells [41].…”

Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting

“…Dose dependent reductions in VEGF-C were observed following cancer cell treatment with an inhibitor of PI3K 19. Aside from a role in angiogenesis, ED-A fibronectin was reported to be upregulated in patient colorectal tumors, especially those that were of advanced stage 20. Investigating CD133 + /CD44 + colorectal tumor cells, a subset of cells believed to be responsible for colon cancer initiation, the authors found that these cells expressed higher levels of the ED-A receptor α 9 β 1 and further demonstrated that ED-A interaction with α 9 β 1 was required for tumor cell proliferation 20.…”

Targeting fibronectin for cancer imaging and therapy

“…On the other hand, the lack of FN in metastatic niche would lead to decreased metastases formation (Figure 2C). For example, a recent study demonstrated that silencing EDA-FN reduced metastasis of colon cancer cells 57 . In companion with EMT, mesenchymal-to-epithelial transition (MET) is also crucial for metastasis formation.…”