The effect of thrombospondin-1 on breast cancer metastasis

Yee, Karen O.; Connolly, Caitlin M.; Duquette, Mark; Kazerounian, Shiva; Washington, Raymond; Lawler, Jack

doi:10.1007/s10549-008-9992-6

Cited by 111 publications

(98 citation statements)

References 57 publications

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“…Hence, in the absence of Tsp-1 production in the lung, Psap failed to suppress metastasis formation by LLC cells. The observed lower numbers of metastases in the Tsp-1 KO mice compared with their wild-type counterparts is consistent with previously reported findings (22) and could be explained by a compensatory 4.5-fold increase in Tsp-2 production induced by LLC cells in these mice, a phenomenon not observed in wild-type mice or human tumors (Figs. S5 and S6).…”

Section: Tsp-1 Expression Is Required For Prosaposin-mediated Suppressupporting

confidence: 92%

Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1

Kang

Halvorsen

Gravdal

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

102

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Metastatic tumors can prepare a distant site for colonization via the secretion of factors that act in a systemic manner. We hypothesized that non- or weakly metastatic human tumor cells may act in an opposite fashion by creating a microenvironment in distant tissues that is refractory to colonization. By comparing cell lines with different metastatic potential, we have identified a tumor-secreted inhibitor of metastasis, prosaposin (Psap), which functions in a paracrine and endocrine fashion by stimulating the expression of thrombospondin-1 (Tsp-1) in fibroblasts present in both primary tumors and distant organs, doing so in a p53-dependent manner. Introduction of Psap in highly metastatic cells significantly reduced the occurrence of metastases, whereas inhibition of Psap production by tumor cells was associated with increased metastatic frequency. In human prostate cancer, decreased Psap expression was significantly associated with metastatic tumors. Our findings suggest that prosaposin, or other agents that stimulate p53 activity in the tumor stroma, may be an effective therapy by inhibition of the metastatic process.

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Section: Tsp-1 Expression Is Required For Prosaposin-mediated Suppressupporting

confidence: 92%

Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1

Kang

Halvorsen

Gravdal

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

102

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“…A number of studies have previously shown that TSP-1 is a mitogeninducible immediate-early response gene (18) and is intimately involved in the regulation of cellular proliferation through effects on integrin pathways (19). Furthermore, consistent with our results, TSP-1 has been shown to be involved in the integrin pathways that can affect tumor cell adhesion (20) or migration/invasion (9).…”

Section: Discussionsupporting

confidence: 89%

“…To determine whether B-Raf V600E could affect ECM composition and drive thyroid cancer progression, we validated various genes linked to invasion and metastasis and focused our in vitro and in vivo validations on TSP-1. TSP-1 and its target TGF-β1 are crucial regulators of epithelial cell growth, motility, polarity, and morphogenesis (9,10) and are important in stromal/epithelial interaction and angiogenesis. Whereas the role of TSP-1 as an inhibitor of tumor angiogenesis is well documented, its biological action in tumor progression and metastasis requires further study (9,10).…”

Section: Discussionmentioning

confidence: 99%

“…TSP-1 and its target TGF-β1 are crucial regulators of epithelial cell growth, motility, polarity, and morphogenesis (9,10) and are important in stromal/epithelial interaction and angiogenesis. Whereas the role of TSP-1 as an inhibitor of tumor angiogenesis is well documented, its biological action in tumor progression and metastasis requires further study (9,10). In this study, TSP-1 was significantly increased in B-Raf V600E -PTCs vs. NT and compared with WT B-Raf PTCs.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, our data indicate that WT B-Raf mRNA silencing in TPC-1 cells (RET/PTC-1) does not affect TSP-1 expression levels, indicating that TSP-1 expression is regulated differently in various cell types and is dependent on genetic context. TSP-1 has many functional domains that interact with a variety of cell surface receptors and can trigger different biological effects in a cell context-dependent manner (9,10). The 3TSR domain plays an important role in activation of TGF-β1 in vivo (9,10).…”

Section: V600ementioning

confidence: 99%

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B-Raf^V600Eand thrombospondin-1 promote thyroid cancer progression

Nucera

Porrello

Antonello

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

160

193

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Although B-Raf V600E is the most common somatic mutation in papillary thyroid carcinoma (PTC), how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-Raf V600E gene set signature associated with tumor progression in PTCs. An independent cohort of B-Raf V600E -positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-1 (TSP-1), because it has been previously shown to be important in the regulation of tumor angiogenesis and metastasis and is present in abundance in tumor stroma. Knockdown of B-Raf V600E resulted in TSP-1 downregulation and a reduction of adhesion and migration/invasion of human thyroid cancer cells. Knockdown of TSP-1 resulted in a similar phenotype. B-Raf V600E cells in which either B-Raf V600E or TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in tumor size and fewer pulmonary metastases from the primary carcinoma as compared with the control cells. Treatment of orthotopic thyroid tumors, initiated 1 week after tumor cell implantation with PLX4720, an orally available selective inhibitor of B-Raf V600E , caused a significant tumor growth delay and decreased distant metastases, without evidence of toxicity. In conclusion, B-Raf V600E plays an important role in PTC progression through genes (i.e., TSP-1) important in tumor invasion and metastasis. Testing of a patient's thyroid cancer for B-Raf V600E will yield important information about potential tumor aggressiveness and also allow for future use of targeted therapies with selective B-Raf V600E inhibitors, such as PLX4720. extracellular matrix | metastasis | papillary thyroid cancer | tumor microenvironment | cell invasion P apillary thyroid cancer (PTC), with its incidence increasing by almost 5% each year, currently ranks as the eighth most common malignancy diagnosed in women (1). Neck recurrences alone are responsible for a third of thyroid cancer-related deaths. There is no effective treatment for radioiodine-resistant metastatic disease; the 10-year survival rate in these cases is only 10% (2). Molecular understanding of the aggressive clinical behavior of this subset of patients is needed to develop new therapeutic options.

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