Treatment for Advanced Tumors: Src Reclaims Center Stage

Summy, Justin M.; Gallick, Gary E.

doi:10.1158/1078-0432.ccr-05-2692

Cited by 202 publications

(152 citation statements)

References 44 publications

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“…As the vast majority of the human deaths in cancer are caused by metastases, most clinical benefit would be obtained by overcoming dissemination and initial steps of metastatic progression. Currently, several Src-kinase inhibitors are in clinical trials (Summy and Gallick, 2006;Kopetz et al, 2007). However, more research is still needed to identify specific and relevant targets for prevention of metastases.…”

Section: Ezrin Regulates Src Phenotype In 3d L Heiska Et Almentioning

confidence: 99%

Ezrin is key regulator of Src-induced malignant phenotype in three-dimensional environment

et al. 2011

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The oncogenic tyrosine kinase Src has a role in cancer development, especially by promoting invasive and metastatic behavior. It is, however, unclear which of the Srcregulated signaling cascades induce malignant phenotype in three-dimensional environment. One of Src substrates is ezrin, a cytoskeletal organiser and regulator of signal transduction. Ezrin expression correlates with poor outcome of diverse cancers and is essential in experimental metastatic osteosarcoma. We reconstituted genetically ezrin-deficient cells with wild-type (WT) or phosphorylation-deficient Y477F ezrin together with constitutively active Src. In two-dimensional cultures, Src induced malignant features regardless of the presence or absence of ezrin. In contrast, only WT ezrin-expressing cells grew efficiently in soft agar or in suspension. In Matrigel, only WT ezrin significantly promoted growth and invasion, and was targeted to specific regions on the plasma membrane. WT and Y477F ezrin-expressing cells showed marked differences only when growing or scattering in threedimensional matrix. Additional experiments showed that Y477-phosphorylated ezrin is also needed for the growth of Src-transformed epithelial cells in three-dimensional matrix. Cells lacking functional ezrin had reduced cyclin D levels and fewer cells in G2 þ S phase, possibly as a consequence of abnormal mTOR signaling, as ezrin Y477F cells showed lower expression of phosphorylated intermediates downstream of mTOR than WT cells. We conclude that the pathways activated by Src depend on the type of environment and that ezrin is a crucial element of Src-induced malignant features in cells growing inside three-dimensional environment.

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Section: Ezrin Regulates Src Phenotype In 3d L Heiska Et Almentioning

confidence: 99%

Ezrin is key regulator of Src-induced malignant phenotype in three-dimensional environment

et al. 2011

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“…The Src signaling pathway is also involved in angiogenesis, cell cycle control and survival. Aberrant expression of activated Src was described in many types of cancer, including lung cancer (Summy and Gallick, 2006). Several Src inhibitors, including saracatinib and dasatinib, are currently investigated in clinical trials (Rothschild et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma

et al. 2012

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“…Potential targets include pathways with well-established inhibitors such as Src and Integrins. Similar to TGF-β, these drugs have both been tested in normal mice and been shown to inhibit osteoclast activity [41,119,120]. Our data suggest that their inhibition may also prevent PTHrP and tumor growth, therefore suggesting that these drugs will target both the tumor and the bone microenvironment.…”

Section: Clinical Perspectivesmentioning

confidence: 69%

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

Guelcher

Sterling

2011

Cancer Microenvironment

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Certain tumors, such as breast, frequently metastasize to bone where they can induce bone destruction. Currently, it is well-accepted that the tumor cells are influenced by other cells and growth factors present in the bone microenvironment that lead to tumor-induced bone disease. Over the past 20 years, many groups have studied this process and determined the major contributing factors; however, these results do not fully explain the changes in gene expression and cell behavior that occur when tumor cells metastasize to bone. More recently, groups studying metastasis from soft tissue sites have determined that the rigidity of the microenvironment, which increases during tumor progression in soft tissue, can regulate tumor cell behavior and gene expression. Therefore, we began to investigate the role of the rigid bone extracellular matrix in the regulation of genes that stimulate tumor-induced bone disease. We found that the rigidity of bone specifically regulates parathyroid hormone-related protein (PTHrP) and Gli2 expression in a transforming growth factor β (TGF-β) and mechanotransduction-dependent mechanism. In this review, we summarize the mechanotransduction signaling pathway and how this influences TGF-β signaling and osteolytic gene expression.

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Treatment for Advanced Tumors: Src Reclaims Center Stage

Cited by 202 publications

References 44 publications

Ezrin is key regulator of Src-induced malignant phenotype in three-dimensional environment

Ezrin is key regulator of Src-induced malignant phenotype in three-dimensional environment

MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

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