Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression

Haga, Ken; Yamazaki, Manabu; Maruyama, Satoshi; Kawaharada, Masami; Suzuki, Ayako; Hoshikawa, Emi; Chan, Nyein Nyein; Funayama, Akinori; Mikami, Toshihiko; Kobayashi, Tadaharu; Izumi, Kenji; Tanuma, Jun‐ichi

doi:10.1016/j.tranon.2021.101236

Cited by 29 publications

(16 citation statements)

References 45 publications

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“…A TGF-β1-mediated EMT could be triggered by SOX9. The invading OSCC cells express a high level of SOX9 products, while at the same time they change the expression of EMT markers, thereby suggesting that SOX9 is the EMT promoter [ 74 ]. Therefore, CAFs may promote cancer migration and invasion via the function of the TGF-β/SOX9 axis.…”

Section: Pro-/anti-inflammatory Cytokinesmentioning

confidence: 99%

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

Kondoh

Mizuno‐Kamiya

2022

Cancers

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HNSCCs are the major progressive malignancy of the upper digestive and respiratory organs. Malignant phenotypes of HNSCCs are regulated by the pro- and anti-tumoral activities of the immune modulatory cytokines associated with TMEs, i.e., a representative pro-inflammatory cytokine, interferon (IFN)-γ, plays a role as an anti-tumor regulator against HNSCCs; however, IFN-γ also drives programmed death-ligand (PD-L) 1 expression to promote cancer stem cells. Interleukin (IL)-2 promotes the cytotoxic activity of T cells and natural killer cells; however, endogenous IL-2 can promote regulatory T cells (Tregs), resulting in the protection of HNSCCs. In this report, we first classified and mentioned the immune modulatory aspects of pro-inflammatory cytokines, pro-/anti-inflammatory cytokines, and anti-inflammatory cytokines upon HNSCC phenotypes. In the TME of HNSCCs, pro-tumoral immune modulation is mediated by stromal cells, including CAFs, MDSCs, pDCs, and TAMs. Therefore, we evaluated the functions of cytokines and chemokines that mediate the crosstalk between tumor cells and stromal cells. In HNSCCs, the status of lymph node metastasis is an important hallmark of a worse prognosis. We therefore evaluated the possibility of chemokines mediating lymph node metastases in HNSCC patients. We also mention therapeutic approaches using anti-tumoral cytokines or immunotherapies that target cytokines, chemokines, or signal molecules essential for the immune evasion of HNSCCs. We finally discuss modulation by HPV infection upon HNSCC phenotypes, as well as the prognostic significance of serum cytokine levels in HNSCC patients.

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Section: Pro-/anti-inflammatory Cytokinesmentioning

confidence: 99%

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

Kondoh

Mizuno‐Kamiya

2022

Cancers

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“…Third, since this work is a preliminary examination of the impact of cellular cholesterol on the activities of OSCC cells, we only evaluated planar cell movement on coverslips. Therefore, planar and vertical migration of cholesterol-manipulated cells will be confirmed in the future using 3D models because OSCC cell migration and invasion also depend on the tumor microenvironment, which can be explored in 3D models [ 59 , 60 ], and are related to the underlying substrates [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Cholesterol Is a Regulator of CAV1 Localization and Cell Migration in Oral Squamous Cell Carcinoma

Chan

Yamazaki

Maruyama

et al. 2023

IJMS

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Cholesterol plays an important role in cancer progression, as it is utilized in membrane biogenesis and cell signaling. Cholesterol-lowering drugs have exhibited tumor-suppressive effects in oral squamous cell carcinoma (OSCC), suggesting that cholesterol is also essential in OSCC pathogenesis. However, the direct effects of cholesterol on OSCC cells remain unclear. Here, we investigated the role of cholesterol in OSCC with respect to caveolin-1 (CAV1), a cholesterol-binding protein involved in intracellular cholesterol transport. Cholesterol levels in OSCC cell lines were depleted using methyl-β-cyclodextrin and increased using the methyl-β-cyclodextrin-cholesterol complex. Functional analysis was performed using timelapse imaging, and CAV1 expression in cholesterol-manipulated cells was investigated using immunofluorescence and immunoblotting assays. CAV1 immunohistochemistry was performed on surgical OSCC samples. We observed that cholesterol addition induced polarized cell morphology, along with CAV1 localization at the trailing edge, and promoted cell migration. Moreover, CAV1 was upregulated in the lipid rafts and formed aggregates in the plasma membrane in cholesterol-added cells. High membranous CAV1 expression in tissue specimens was associated with OSCC recurrence. Therefore, cholesterol promotes the migration of OSCC cells by regulating cell polarity and CAV1 localization to the lipid raft. Furthermore, membranous CAV1 expression is a potential prognostic marker for OSCC patients.

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“…It is widely accepted that CAFs are crucial in the occurrence, development, invasion and metastasis of OSCC ( Erdogan and Webb, 2017 ; Haga et al, 2021 ). Therefore, it is important to explore whether HF could inhibit the migration and invasion of OSCC cells by affecting CAFs.…”

Section: Discussionmentioning

confidence: 99%

“…Halofuginone is an alkaloid derived from quinazolinone with a low molecular weight that has a significant antifibrotic effect and can inhibit the production of type I collagen and reverse the (Erdogan and Webb, 2017;Haga et al, 2021). Therefore, it is important to explore whether HF could inhibit the migration and invasion of OSCC cells by affecting CAFs.…”

Section: Discussionmentioning

confidence: 99%

Halofuginone inhibits tumor migration and invasion by affecting cancer-associated fibroblasts in oral squamous cell carcinoma

Wang

Tian

et al. 2022

Front. Pharmacol.

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Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial regions, with a high rate of metastasis. Cancer-associated fibroblasts (CAFs) play critical roles in tumor growth, metastasis and invasion, making them attractive therapeutic targets for cancer treatment. As an old anti-coccidiosis drug for poultry, Halofuginone (HF) has also been reported to possess anti-fibrosis and anti-cancer activities in the recent decades. However, whether it works by targeting CAFs in OSCC, and the mechanisms involved remain unclear. In the present study, we observed HF dose-dependently inhibits OSCC-derived CAF viability and proliferation. Meanwhile, HF decreased the expressions of α-SMA, FSP-1 and PDGFRβ, markers of the malignant phenotype of CAFs, both at mRNA and protein levels. Furthermore, functional studies demonstrated that HF dramatically attenuates the promotion effect of CAFs on OSCC cell migration and invasion. Mechanistically, the inhibition of MMP2 secretion and the upstream TGF-β/Smad2/3 signaling pathway played an important role in these processes. In the orthotopic transplanted tongue carcinoma in mice model, we confirmed that HF administration inhibited tumor growth and lymph node metastasis (LNM) with reduced CAF population, MMP2 expression and collagen deposition in tumor. Altogether, these results indicate that HF can inhibit the migration and invasion of OSCC by targeting CAFs, which will provide new ideas for the treatment of OSCC.

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Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression

Cited by 29 publications

References 45 publications

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

Cholesterol Is a Regulator of CAV1 Localization and Cell Migration in Oral Squamous Cell Carcinoma

Halofuginone inhibits tumor migration and invasion by affecting cancer-associated fibroblasts in oral squamous cell carcinoma

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