Overexpression of thrombospondin‐1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma

Lin, Xiandong; Chen, Shuqin; Qi, Yuanlin; Zhu, Jin; Yang, Tao; Lin, Jianghai

doi:10.1002/jso.23037

Cited by 39 publications

(36 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…THBS1 protein was located in tumor cells and was undetectable in stroma. This contrasts with gastric cancer, where THBS1 localized to stroma [62], indicating apparent tissue-specific differences depending on cancer type.…”

Section: Discussionmentioning

confidence: 99%

Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma

et al. 2014

View full text Add to dashboard Cite

Epithelial-to-mesenchymal transition (EMT), in which epithelial cells loose their polarity and become motile mesenchymal cells, is a determinant of melanoma metastasis. We compared gene expression signatures of mesenchymal-like melanoma cells with those of epithelial-like melanoma cells, and identified Thrombospondin 1 (THBS1) as highly up-regulated in the mesenchymal phenotype. This study investigated whether THBS1, a major physiological activator of transforming growth factor (TGF)-beta, is involved in melanoma EMT-like process. We sought to examine expression patterns in distinct melanoma phenotypes including invasive, de-differentiated, label-retaining and drug resistant populations that are putatively associated with an EMT-like process.Here we show that THBS1 expression and secretion was elevated in melanoma cells exhibiting invasive, drug resistant, label retaining and mesenchymal phenotypes and correlated with reduced expression of genes involved in pigmentation. Elevated THBS1 levels were detected in Vemurafenib resistant melanoma cells and inhibition of THBS1 led to significantly reduced chemoresistance in melanoma cells. Notably, siRNA-mediated silencing of THBS1 and neutralizing antibody to THBS1 reduced invasion in mesenchymal-like melanoma cells, while ectopic THBS1 expression in epithelial-like melanoma cells enhanced invasion. Furthermore, the loss of THBS1 inhibited in vivo motility of melanoma cells within the embryonic chicken neural tube. In addition, we found aberrant THBS1 protein expression in metastatic melanoma tumor biopsies. These results implicate a role for THBS1 in EMT, and hence THBS1 may serve as a novel target for strategies aimed at the treatment of melanoma invasion and drug resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Yet, extensive literature presents loss of TSP-1 expression during malignant progression as a hallmark of the ''angiogenic switch'' in a variety of major cancer types [3], with TSP-1 being typically down-regulated under oncogenes activation [4]. Among the hypothetical reasons that could explain high TSP-1 plasma concentrations, some have suggested that TSP-1 may originate from tumor stromal compartment [5]. Nevertheless, one should consider melanoma an exception as melanoma cells also express TSP-1 while their normal counterparts do not [6,7].…”

Section: Introductionmentioning

confidence: 99%

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

Jeanne

Boulagnon‐Rombi

Devy

et al. 2016

Clin Exp Metastasis

View full text Add to dashboard Cite

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.

show abstract

“…Clearly, further studies are required to confirm these hypotheses. THBS1 has been reported to exert a pro-angiogenic effect in gastric cancer (13)(14)(15)(16)(17), which plays an important role in cancer metastasis. Tumor metastasis is well established as a critical event affecting patient prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have correlated THBS1 expression to tumor angiogenesis, tumor growth and metastasis (8)(9)(10)(11)(12). In gastric cancer, THBS1 may have a pro-angiogenic effect, and elevated THBS1 expression levels have been associated with gastric cancer tumor growth and lymph node metastasis (13)(14)(15)(16)(17). However, thus far, genetic evidence of a role for THBS1 in gastric cancer is lacking.…”

Section: Introductionmentioning

confidence: 99%

Association of THBS1 rs1478605 T>C in 5′-untranslated regions with the development and progression of gastric cancer

Chen

et al. 2015

Biomedical Reports

Self Cite

View full text Add to dashboard Cite

Thrombospondin 1 (THBS1) plays an important role in angiogenesis and tumor progression. The aim of the present study was to investigate the effects of single-nucleotide polymorphisms (rs1478605 and rs3743125) in the untranslated regions of the gene on the development and progression of gastric cancer. In the case-control study, 275 gastric cancer patients and 275 cancer-free controls were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism. The data demonstrated that rs1478605 genotypic distributions significantly differed between the patient and control groups (P=0.005). Carriers of the CC genotype exhibited a decreased risk of developing gastric cancer compared to the carriers of the CT and TT genotypes [adjusted odd ratio (OR), 0.56; 95% confidence interval (CI), 0.39-0.79; P=0.001]. The CC genotype of rs1478605 was negatively associated with gastric cancer lymph node metastasis (OR, 0.41; 95% CI, 0.23-0.71; P=0.001) and was associated with a reduced risk of lymph node metastasis in male patients (OR, 0.27; 95% CI, 0.14-0.52; P<0.001). The CT haplotype was associated with a reduced risk of developing gastric cancer (OR, 0.56; 95% CI, 0.33-0.93; P=0.02). By contrast, no association was observed between rs3743125 and the development and progression of gastric cancer. These results suggest that rs1478605 represents apotential molecular marker for gastric cancer.

show abstract

Overexpression of thrombospondin‐1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma

Cited by 39 publications

References 39 publications

Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma

Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

Association of THBS1 rs1478605 T>C in 5′-untranslated regions with the development and progression of gastric cancer

Contact Info

Product

Resources

About