Suppression of TGF<sub>β</sub>and Angiogenesis by Type VII Collagen in Cutaneous SCC

Martins, Vera; Caley, Matthew; Moore, Kate M.; Szentpétery, Zsófia; Marsh, Sydney; Murrell, Dédée F.; Kim, M H; Avari, Malcolm; McGrath, John A.; Cerio, R.; Kivisaari, Atte; Kähäri, Veli‐Matti; Hodivala‐Dilke, Kairbaan; Brennan, Caroline H.; Chen, M; Marshall, John F.; O’Toole, Edel A.

doi:10.1093/jnci/djv293

Cited by 69 publications

(85 citation statements)

References 49 publications

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“…Our data indicated that platelet Tgfβ1 is important for neoangiogenesis inside orthotopic tumors in murine models of ovarian cancer. This observation is consistent with a recent study reporting a reduction in endothelial cells tube formation after inhibition of Tgfβ1 receptor signaling in an in vitro assay (23). Tgfβ1 regulates tumor angiogenesis by upregulating expression and activity of two potent proangiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (24–26).…”

Section: Discussionsupporting

confidence: 93%

Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

Hisamatsu

Haemmerle

et al. 2017

Clinical Cancer Research

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Purpose Transforming growth factor β1 (Tgfβ1) plays an important role in cancer. Most of Tgfβ1 in plasma is from platelets, thus we studied whether platelet Tgfβ1 has any role in the progression of ovarian cancer, and whether this role is limited to metastasis or also involves the growth of primary tumors. Experimental Design We compared the growth of murine ovarian cancer cell-induced tumors in platelet-specific Tgfβ1 deficient mice and wild-type mice. Using resected tumor nodules, we studied the effect of platelet Tgfβ1 on neoangiogenesis and on platelet extravasation into tumors. To investigate the effect of Tgfβ1 at different stages of ovarian cancer, we reduced expression of Tgfβ1 receptor (its TgfβR1 component) in tumors at different time points after injection of cancer cells, and compared the final tumor size. Results Lack of platelet Tgfβ1 in mice reduced tumor growth, neoangiogenesis, and platelet extravasation. Ovarian cancer tumors in platelet-specific Tgfβ1 deficient mice reached less than half of their size in wild-type littermates. Knockdown of TgfβR1on cancer cells in the first 2 weeks after their injection reduced tumor growth, but was less effective if initiated after 3 weeks. Conclusions We showed that platelet Tgfβ1 increased the growth of primary tumors in murine models of ovarian cancer. We also showed that inhibition of TgfβR1 is more effective in reducing the growth of ovarian cancer if initiated earlier. Our results supported a therapeutic benefit in preventing platelet activation, degranulation, and release of Tgfβ1 in ovarian cancer.

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Section: Discussionsupporting

confidence: 93%

Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

Hisamatsu

Haemmerle

et al. 2017

Clinical Cancer Research

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“…A). An RDEB‐specific cSCC line, namely, EB3K , had no expression of C7 and was also included in this study together with fibroblasts and keratinocytes from healthy donors and patients with RDEB.…”

Section: Resultsmentioning

confidence: 99%

Cord Blood-Derived Stem Cells Suppress Fibrosis and May Prevent Malignant Progression in Recessive Dystrophic Epidermolysis Bullosa

et al. 2018

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Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by mutations in the Col7a1 gene. Patients with RDEB suffer from recurrent erosions in skin and mucous membranes and have a high risk for developing cutaneous squamous cell carcinoma (cSCCs). TGFβ signaling has been associated with fibrosis and malignancy in RDEB. In this study, the activation of TGFβ signaling was demonstrated in col7a1−/− mice as early as a week after birth starting in the interdigital folds of the paws, accompanied by increased deposition of collagen fibrils and elevated dermal expression of matrix metalloproteinase (MMP)‐9 and MMP‐13. Furthermore, human cord blood‐derived unrestricted somatic stem cells (USSCs) that we previously demonstrated to significantly improve wound healing and prolong the survival of col7a1−/− mice showed the ability to suppress TGFβ signaling and MMP‐9 and MMP‐13 expression meanwhile upregulating anti‐fibrotic TGFβ3 and decorin. In parallel, we cocultured USSCs in a transwell with RDEB patient‐derived fibroblasts, keratinocytes, and cSCC, respectively. The patient‐derived cells were constitutively active for STAT, but not TGFβ signaling. Moreover, the levels of MMP‐9 and MMP‐13 were significantly elevated in the patient derived‐keratinocytes and cSCCs. Although USSC coculture did not inhibit STAT signaling, it significantly suppressed the secretion of MMP‐9 and MMP‐13, and interferon (IFN)‐γ from RDEB patient‐derived cells. Since epithelial expression of these MMPs is a biomarker of malignant transformation and correlates with the degree of tumor invasion, these results suggest a potential role for USSCs in mitigating epithelial malignancy, in addition to their anti‐inflammatory and anti‐fibrotic functions. Stem Cells 2018;36:1839–12

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“…The cellular phenotype may vary depending on COL7 expression levels, demonstrated when overexpression of COL7 in RDEB cells exceeds the physiological level of the protein . Terminal differentiation of RDEB‐SCC cells is suppressed in vivo and in xenograft models …”

Section: Col7 In Wound Healing and Carcinogenesis Of Keratinocytesmentioning

confidence: 99%

Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita

Watanabe

Natsuga

Shinkuma

et al. 2018

The Journal of Dermatology

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Type VII collagen (COL7), a major component of anchoring fibrils in the epidermal basement membrane zone, has been characterized as a defective protein in dystrophic epidermolysis bullosa and as an autoantigen in epidermolysis bullosa acquisita. Although COL7 is produced and secreted by both epidermal keratinocytes and dermal fibroblasts, the role of COL7 with regard to the epidermis is rarely discussed. This review focuses on COL7 physiology and pathology as it pertains to epidermal keratinocytes. We summarize the current knowledge of COL7 production and trafficking, its involvement in keratinocyte dynamics, and epidermal carcinogenesis in COL7 deficiency and propose possible solutions to unsolved issues in this field.

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Suppression of TGF_βand Angiogenesis by Type VII Collagen in Cutaneous SCC

Abstract: Type VII collagen suppresses TGFβ signaling and angiogenesis in cutaneous SCC. Patients with RDEB SCC may benefit from anti-angiogenic therapy.

Cited by 69 publications

References 49 publications

Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

Cord Blood-Derived Stem Cells Suppress Fibrosis and May Prevent Malignant Progression in Recessive Dystrophic Epidermolysis Bullosa

Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita

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Suppression of TGFβand Angiogenesis by Type VII Collagen in Cutaneous SCC

Abstract: Type VII collagen suppresses TGFβ signaling and angiogenesis in cutaneous SCC. Patients with RDEB SCC may benefit from anti-angiogenic therapy.

Cited by 69 publications

References 49 publications

Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

Cord Blood-Derived Stem Cells Suppress Fibrosis and May Prevent Malignant Progression in Recessive Dystrophic Epidermolysis Bullosa

Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita

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Suppression of TGF_βand Angiogenesis by Type VII Collagen in Cutaneous SCC