The Loss of TGF-β Signaling Promotes Prostate Cancer Metastasis

Tu, William H.; Thomas, Tania Z.; Masumori, Naoya; Bhowmick, Neil A.; Gorska, Agnieszka E.; Shyr, Yu; Kasper, Susan; Case, Thomas C.; Roberts, Richard L.; Shappell, Scott B.; Moses, Harold L.; Matusik, Robert J.

doi:10.1016/s1476-5586(03)80058-1

Cited by 98 publications

(62 citation statements)

References 16 publications

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“…These authors argue that the TGFb may provide an additional boost to tumor progression by dampening the immune response to the tumors [99]. Corroborating these mouse model results, other researchers demonstrated that expression of a dominant-negative TGFBR2 in tumor cells enhanced metastasis in a mouse prostate tumor model [100]. These results conflict with the previously described research and suggest that the role of TGFb in metastasis depends on multiple factors, including the tumor-initiating mutation, method of TGFb inactivation, and the timing of the TGFb signal.…”

Section: Mouse Models Of Tgfβ and Metastasismentioning

confidence: 92%

Roles of TGFβ in metastasis

2008

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The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGFβ can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFβ signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFβ therapies are currently being developed and tested in preclinical studies. However, targeting TGFβ carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFβ has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFβ inhibitors for clinical use will require a deeper understanding of TGFβ signaling, its consequences, and the contexts in which it acts.

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Section: Mouse Models Of Tgfβ and Metastasismentioning

confidence: 92%

Roles of TGFβ in metastasis

2008

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“…48 For instance, BMP7 was shown to counteract EMT by inducing MET, to induce EMT, or to have no effect. 2,4,10,49,51 In the noncancerous human prostate, expression of BMP7 protein was restricted mainly to the glandular epithelium, whereas primary prostate cancers show low or undetectable BMP7 protein expression.…”

Section: Bmp7 and Prostatementioning

confidence: 99%

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

Buijs

Rentsch

Horst

et al. 2007

The American Journal of Pathology

181

161

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Bone morphogenic protein 7 (BMP7) counteracts physiological epithelial-to-mesenchymal transition, a process that is indicative of epithelial plasticity. Because epithelial-to-mesenchymal transition is involved in cancer, we investigated whether BMP7 plays a role in prostate cancer growth and metastasis. BMP7 expression in laser-microdissected primary human prostate cancer tissue was strongly down-regulated compared with normal prostate luminal epithelium. Furthermore, BMP7 expression in prostate cancer cell lines was inversely related to tumorigenic and metastatic potential in vivo and significantly correlated to E-cadherin/vimentin ratios. Exogenous addition of BMP7 to human prostate cancer cells dose-dependently inhibited transforming growth factor ␤-induced activation of nuclear Smad3/4 complexes via ALK5 and induced E-cadherin expression. Moreover, BMP7-induced activation of nuclear Smad1/4/5 signaling transduced via BMP type I receptors was synergistically stimulated in the presence of transforming growth factor ␤, a growth factor that is enriched in the bone microenvironment. Daily BMP7 administration to nude mice inhibited the growth of cancer cells in bone. In contrast, no significant growth inhibitory effect of BMP7 was observed in intraprostatic xenografts. Collectively, our observations suggest that BMP7 controls and preserves the epithelial phenotype

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“…Decreased breast cancer metastasis was seen in a model expressing a dominant negative TGF-βRII (∆βRII) transgene in human breast-derived cell lines (10). In contrast, increased skin cancer metastasis and prostate cancer metastasis were observed in the respective ∆βRII-transgenic models (11,12). Clinical studies also reveal controversial results regarding patient outcome when the prognosis is correlated with the loss of TGF-βRII in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Distinct mechanisms of TGF- 1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

Han¹

2005

Journal of Clinical Investigation

210

186

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In the present study, we demonstrated that human skin cancers frequently overexpress TGF-β 1 but exhibit decreased expression of the TGF-β type II receptor (TGF-βRII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-β 1 in keratinocytes expressing a dominant negative TGF-βRII (∆βRII) in the epidermis. Without ∆βRII expression, TGF-β 1 transgene induction in late-stage, chemically induced papillomas failed to inhibit tumor growth but increased metastasis and epithelial-to-mesenchymal transition (EMT), i.e., formation of spindle cell carcinomas. Interestingly, ∆βRII expression abrogated TGF-β 1 -mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-β 1 /∆βRII compound tumors. Furthermore, expression of molecules thought to mediate TGF-β 1 -induced EMT was attenuated in TGF-β 1 /∆βRII-transgenic tumors. However, TGF-β 1 /∆βRII-transgenic tumors progressed to metastasis without losing expression of the membrane-associated E-cadherin/catenin complex and at a rate higher than those observed in nontransgenic, TGF-β 1 -transgenic, or ∆βRII-transgenic mice. Abrogation of Smad activation by ∆βRII correlated with the blockade of EMT. However, ∆βRII did not alter TGF-β 1 -mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-β 1 induces EMT and invasion via distinct mechanisms. TGF-β 1 -mediated EMT requires functional TGF-βRII, whereas TGF-β 1 -mediated tumor invasion cooperates with reduced TGF-βRII signaling in tumor epithelia.

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The Loss of TGF-β Signaling Promotes Prostate Cancer Metastasis

Cited by 98 publications

References 16 publications

Roles of TGFβ in metastasis

Roles of TGFβ in metastasis

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

Distinct mechanisms of TGF- 1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

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