CD44 Expressed on Cancer-Associated Fibroblasts Is a Functional Molecule Supporting the Stemness and Drug Resistance of Malignant Cancer Cells in the Tumor Microenvironment

Abstract

Cells constituting the tumor microenvironment are attractive targets for developing new cancer therapies. Here we show that cancer-associated fibroblasts (CAFs) support tumor growth in vivo and maintain the stemness of cancer stem/initiating cells in an in vitro model using an established CAF cell line. We found that CD44 is abundantly expressed on CAFs. This molecule is a cancer stem cell marker in several tumors, but its role in tumorigenesis when expressed by CAFs has not been investigated. It is generally accepted that hypoxic and hyponutritional conditions are triggers of cancer malignancy. We found that CAFs strongly express CD44 in hypoxic and avascular areas in the tumor and that its expression on established CAFs is upregulated under hypoxic and hyponutritional conditions in vitro. In addition, CAF CD44-positivity in tumor tissues was increased after treatment with inhibitors of angiogenesis. Using cocultures and tumor sphere formation assays, CAFs from wild-type mice were found to sustain the stemness of cancer stem/initiating cells, while CD44-deficient CAFs did not. Furthermore, CD44 was involved in malignant cancer cell drug resistance mechanisms. In conclusion, our study suggests that CD44 on CAFs is a functional molecule contributing to the maintenance of cancer stem cell populations in the tumor microenvironment. STEM CELLS 2014;32:145-156

Extreme low dose of 5-fluorouracil reverses MDR in cancer by sensitizing cancer associated fibroblasts and down-regulating P-gp

“…There is growing evidence that CAFs sustain the stemness of cancer cells, stemness being involved in cancer cell drug resistance mechanisms [17–19]. We therefore explored the status of CAFs after treatment using immunofluorescence staining of α-smooth muscle actin (α-SMA), a marker for CAFs.…”

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…CAFs have been also reported to mediate resistance to anti-angiogenic therapy (Pietras et al 2008) or MMP-mediated cetuximab resistance in head and neck squamous cell carcinoma cells (Johansson et al 2012). They can adopt decoy strategies such as expression of CD44, a cell surface protein normally expressed in epithelial cells, to support stemness and drug resistance of malignant cancer cells (Kinugasa et al 2014). The simultaneous targeting of tumor stroma and epithelial cancer cells with combination therapies may be a successful therapeutic approach for treating various cancers while overcoming drug resistance.…”

Evaluation of PSF1 as a prognostic biomarker for prostate cancer

“…They were also resistant to chemotherapeutic agents, and formed spheres when cultured. 21,22 Their gene expression profiles were embryonic stem cell-like. 20 These data suggest that cancer cells strongly expressing PSF1 possess cancer stem cell-like properties and high malignancy.…”

“…20 Moreover, cells with high PSF1 transcriptional activity formed tumor spheres more efficiently in vitro, had an embryonic stem cell-like gene expression profile and showed greater drug resistance after administration of anti-cancer drugs. [20][21][22] Thus far, although PSF1 promoter activity was shown to correlate with malignancy of cancer cells, PSF1 expression in human cancer has not been closely examined. Here, we analyzed PSF1 expression in human prostate cancer and evaluated the relationship between its expression on needle biopsy specimens and clinical features such as PSA value, Gleason score and clinical stage, as well as prognosis.…”