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The role of TGF-? in bone metastasis: novel therapeutic perspectives.

ABSTRACT: The skeleton is a preferred site for cancer metastasis. These bone metastases cause dysregulated bone remodeling and the associated morbidity of fractures, pain, hypercalcemia and catastrophic nerve compression syndromes. Transforming growth factor-? (TGF-?) is stored in mineralized bone matrix, and released and activated by osteoclastic bone resorption. Once activated, TGF-? stimulates nearby metastatic tumor cells within the bone microenvironment to secrete factors that further drive osteolytic destruction of the bone. Therefore, TGF-? and its signaling constitute a critical component driving the feed-forward vicious cycle of cancer growth in bone. Moreover, additional pro-tumorigenic activities attributed to TGF-? include activation of epithelial-to-mesenchymal transition, increased tumor cell invasion, enhanced angiogenesis and various immunomodulatory properties. Blocking the TGF-? signaling pathway to interrupt this vicious cycle and manipulate the bone microenvironment offers a promising area for therapeutic intervention to decrease skeletal metastasis and normalize bone homeostatic mechanisms. In this review, preclinical and clinical data are evaluated for the potential use of TGF-? pathway inhibitors in clinical practice to treat bone metastases and its associated comorbidities.

SUBMITTER: Buijs JT

PROVIDER: S-EPMC3727840 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The role of TGF-β in bone metastasis: novel therapeutic perspectives.

Buijs Jeroen T JT Stayrook Keith R KR Guise Theresa A TA

BoneKEy reports 20120606

The skeleton is a preferred site for cancer metastasis. These bone metastases cause dysregulated bone remodeling and the associated morbidity of fractures, pain, hypercalcemia and catastrophic nerve compression syndromes. Transforming growth factor-β (TGF-β) is stored in mineralized bone matrix, and released and activated by osteoclastic bone resorption. Once activated, TGF-β stimulates nearby metastatic tumor cells within the bone microenvironment to secrete factors that further drive osteolyti ...[more]

PMID: 23951484

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Project description:IntroductionMammary tumorigenesis is associated with the increased expression of several proteins in the focal adhesion complex, including focal adhesion kinase (FAK) and various integrins. Aberrant expression of these molecules occurs concomitant with the conversion of TGF-beta function from a tumor suppressor to a tumor promoter. We previously showed that interaction between beta3 integrin and TbetaR-II facilitates TGF-beta-mediated oncogenic signaling, epithelial-mesenchymal transition (EMT), and metastasis. However, the molecular mechanisms by which the focal adhesion complex contributes to beta3 integrin:TbetaR-II signaling and the oncogenic conversion of TGF-beta remain poorly understood.MethodsFAK expression and activity were inhibited in normal and malignant mammary epithelial cells (MECs) either genetically by using lentiviral-mediated delivery of shRNAs against FAK, or pharmacologically through in vitro and in vivo use of the FAK inhibitors, PF-562271 and PF-573228. Altered Smad2/3 and p38 MAPK activation, migration, EMT, and invasion in response to TGF-beta1 were monitored in FAK-manipulated cells. TbetaR-II expression was increased in metastatic breast cancer cells by retroviral transduction, and the metastasis of FAK- and TbetaR-II-manipulated tumors was monitored by using bioluminescent imaging.ResultsTGF-beta stimulation of MECs stabilized and activated FAK in a beta3 integrin- and Src-dependent manner. Furthermore, by using the human MCF10A breast cancer progression model, we showed that increased FAK expression in metastatic breast cancer cells mirrored the acquisition of enhanced activation of p38 MAPK by TGF-beta. Administering FAK inhibitors or rendering metastatic breast cancer cells FAK deficient abrogated the interaction between beta3 integrin and TbetaR-II, thereby preventing TGF-beta from (a) activating p38 MAPK; (b) stimulating MEC invasion, migration, and EMT; and (c) inducing early primary tumor dissemination to the lungs. Finally, in contrast to FAK depletion, adjuvant FAK chemotherapy of mammary tumors decreased their growth in part by diminished macrophage tumor infiltration.ConclusionsOur studies identify an essential function for FAK in mediating the interaction between beta3 integrin and TbetaR-II, and thus in facilitating the oncogenic conversion of TGF-beta required for mammary tumor metastasis. Furthermore, this study establishes chemotherapeutic targeting of FAK as an effective, two-pronged approach in preventing tumor progression both by decreasing innate immune cell infiltration, and by inhibiting early TGF-beta-dependent metastasis.

Dataset Information

The role of TGF-? in bone metastasis: novel therapeutic perspectives.

Publications

The role of TGF-β in bone metastasis: novel therapeutic perspectives.

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