Targeting CTGF in Cancer: An Emerging Therapeutic Opportunity

Shen, Yiwen; Zhou, Yifeng; Chen, Hongzhuan; Luan, Xin; Zhang, Weidong

doi:10.1016/j.trecan.2020.12.001

Cited by 59 publications

(56 citation statements)

References 100 publications

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“…64,65 Here, CTGF, a matricellular protein which has a potential role in the tumor microenvironment was also regulated by FOXD1. 66 These findings suggest that FOXD1 may have a potential function in modulating the tumor microenvironment. Therefore, more in-depth investigation of the interplay between FOXD1 and the melanoma microenvironment will hopefully lead to more effective ways of treating metastatic melanoma and preventing drug resistance.…”

Section: Discussionmentioning

confidence: 93%

FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of connective tissue growth factor

Sun

Novak

Hüser

et al. 2021

Intl Journal of Cancer

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Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAF V600E -mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. We previously demonstrated that forkhead box D1 (FOXD1) regulates melanoma migration and invasion. Here, we found that FOXD1 was highly expressed in melanoma cells and was associated with a poor survival of patients with metastatic melanoma. Upregulation of FOXD1 expression enhanced melanoma cells' resistance to vemurafenib (BRAF inhibitor [BRAFi]) or vemurafenib and cobimetinib (MEK inhibitor) combination treatment whereas loss of FOXD1 increased the sensitivity to treatment. By comparing gene expression levels between FOXD1 knockdown (KD) and overexpressing (OE) cells, we identified the connective tissue growth factor (CTGF) as a downstream factor of FOXD1. Chromatin immunoprecipitation and luciferase assay demonstrated the direct binding of FOXD1 to the CTGF promoter. Similar to FOXD1, knockdown of CTGF increased the sensitivity of BRAFi-resistant cells to vemurafenib. FOXD1 KD cells treated with recombinant CTGF protein were less sensitive towards vemurafenib compared to untreated FOXD1 KD cells. Based on these findings, we conclude that FOXD1 might be a promising new diagnostic marker and a therapeutic target for the treatment of targeted therapy resistant melanoma.

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Section: Discussionmentioning

confidence: 93%

FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of connective tissue growth factor

Sun

Novak

Hüser

et al. 2021

Intl Journal of Cancer

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“…Because we are going to study the mechanism of ATL-1 on chemosensitization, the examination of these genes can provide ideas for us. For example, SOX9 is a key transcription factor and related with chemoresistance ( 46 ); HMGB2 is known to bind to DNA structure resulting from cisplatin-DNA adducts and affect the chemosensitivity of cells ( 47 ); CD44 is related with stemness of cancer cells ( 48 ); S100A4 and CTGF are related with fibroblast in tumor microenvironment ( 43 , 49 ). We chose CTGF for further study because it might help us to explain the chemosensitization function of ATL-1 from aspect of microenvironment and CAF.…”

Section: Discussionmentioning

confidence: 99%

Atractylenolide-I Sensitizes Triple-Negative Breast Cancer Cells to Paclitaxel by Blocking CTGF Expression and Fibroblast Activation

Wang

Zhang

et al. 2021

Front. Oncol.

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This investigation was conducted to elucidate whether atractylenolide-I (ATL-1), which is the main component of Atractylodes macrocephala Koidz, can sensitize triple-negative breast cancer (TNBC) cells to paclitaxel and investigate the possible mechanism involved. We discovered that ATL-1 could inhibit tumor cell migration and increase the sensitivity of tumor cells to paclitaxel. ATL-1 downregulated the expression and secretion of CTGF in TNBC cells. Apart from inhibiting TNBC cell migration via CTGF, ATL-1 downregulated the expression of CTGF in fibroblasts and decreased the ability of breast cancer cells to transform fibroblasts into cancer-associated fibroblasts (CAFs), which in turn increased the sensitivity of TNBC cells to paclitaxel. In a mouse model, we found that ATL-1 treatments could enhance the chemotherapeutic effect of paclitaxel on tumors and reduce tumor metastasis to the lungs and liver. Primary cultured fibroblasts derived from inoculated tumors in mice treated with ATL-1 combined with paclitaxel expressed relatively low levels of CAF markers. Collectively, our data indicate that ATL-1 can sensitize TNBC cells to paclitaxel by blocking CTGF expression and fibroblast activation and could be helpful in future research to determine the value of ATL-1 in the clinical setting.

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“…CTGF, a CCN family member, performs chemotaxis, induces adhesion, and regulates cell proliferation and migration ( Ramazani et al, 2018 ; Shen et al, 2021 ). CTGF also regulates bone formation in the cartilage ( Takigawa et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

“…Research has also proven that CTGF is the main regulator of cartilage formation. The multidomain feature allows CTGF to interact with other growth factors such as TGF-β, BMP, IGF, and VEGF ( Shen et al, 2021 ). Simultaneously, CTGF interacts with the extracellular matrix and cell surface receptors, such as integrins ( Perbal, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Connective Tissue Growth Factor From Periosteal Tartrate Acid Phosphatase-Positive Monocytes Direct Skeletal Stem Cell Renewal and Fate During Bone Healing

Bai

Deng

et al. 2021

Front. Cell Dev. Biol.

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The periosteum is critical for bone healing. Studies have shown that the periosteum contains periosteal stem cells (PSCs) with multidirectional differentiation potential and self-renewal ability. PSCs are activated in early fracture healing and are committed to the chondrocyte lineage, which is the basis of callus formation. However, the mechanism by which PSCs are activated and committed to chondrocytes in bone regeneration remains unclear. Here, we show that tartrate acid phosphatase (TRAP)-positive monocytes secrete CTGF to activate PSCs during bone regeneration. The loss function of TRAP-positive monocytes identifies their specific role during bone healing. Then, the secreted CTGF promotes endochondral ossification and activates PSCs in mouse bone fracture models. The secreted CTGF enhances PSC renewal by upregulating the expression of multiple pluripotent genes. CTGF upregulates c-Jun expression through αVβ5 integrin. Then, c-Jun transcription activates the transcription of the pluripotent genes Sox2, Oct4, and Nanog. Simultaneously, CTGF also activates the transcription and phosphorylation of Smad3 through αVβ5 integrin, which is the central gene in chondrogenesis. Our study indicates that TRAP-positive monocyte-derived CTGF promotes bone healing by activating PSCs and directing lineage commitment and that targeting PSCs may be an effective strategy for preventing bone non-union.

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Targeting CTGF in Cancer: An Emerging Therapeutic Opportunity

Cited by 59 publications

References 100 publications

FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of connective tissue growth factor

FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of connective tissue growth factor

Atractylenolide-I Sensitizes Triple-Negative Breast Cancer Cells to Paclitaxel by Blocking CTGF Expression and Fibroblast Activation

Connective Tissue Growth Factor From Periosteal Tartrate Acid Phosphatase-Positive Monocytes Direct Skeletal Stem Cell Renewal and Fate During Bone Healing

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