Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model

Slack‐Davis, Jill K.; Hershey, E. Daniel; Theodorescu, Dan; Frierson, Henry F.; Parsons, John T.

doi:10.1158/1535-7163.mct-09-0262

Cited by 46 publications

(48 citation statements)

References 22 publications

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“…membrane, our results support the model that prostate tumors contain a basal compartment consisting of putative stem cells able to undergo self-renewal as well as transit-amplifying cells undergoing rapid proliferation. In agreement with the hypothesis that integrin β4 signaling plays a unique role in prostate tumorigenesis, others have shown that genetic ablation of FAK does not impair tumor initiation or progression to adenocarcinoma in PB-TAg mice (80), suggesting that the β1 integrin/FAK signaling axis does not contribute to prostate tumorigenesis.…”

Section: Figuresupporting

confidence: 72%

β4 Integrin signaling induces expansion of prostate tumor progenitors

Yoshioka¹,

Otero²,

Chen³

et al. 2013

J. Clin. Invest.

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The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted IntroductionProstate cancer, the most common noncutaneous malignancy diagnosed in men, progresses from carcinoma in situ, termed prostatic intraepithelial neoplasia (PIN), to invasive and metastatic cancer, suggesting that multiple genetic and epigenetic lesions contribute to its development. Although significant progress has been made toward early detection and treatment, once it has become metastatic, prostate cancer cannot be cured (1, 2). Patterns of allelic loss in human prostate cancer specimens and reverse genetic approaches in the mouse have suggested that loss of function mutations in NKX3.1, PTEN, RB, and P53 and overexpression of MYC promote prostate cancer progression (3). Studies using outlier gene expression analysis have revealed that oncogenic gene fusions juxtaposing 5′ androgen-controlled regulatory elements to Ets transcription factors, such as ERG, are prevalent in human prostate cancer (4). In addition, integrative genomic profiling of a large data set (n = 218) has provided evidence that allelic losses and gains disrupting the Rb and p53 signaling networks and activating the PI-3K and the Ras/Raf signaling pathways are also common in primary prostate cancers, whereas amplifications and mutations of the androgen receptor (AR) are restricted to metastatic lesions (5).Increasing evidence suggests that oncogenic mutations exert their action by transforming adult stem cells or transit-amplifying cells into neoplastic progenitor cells, thereby spurring the develop-

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Section: Figuresupporting

confidence: 72%

β4 Integrin signaling induces expansion of prostate tumor progenitors

Yoshioka¹,

Otero²,

Chen³

et al. 2013

J. Clin. Invest.

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“…Recently, researchers started to carefully look into the molecular pathways involved in two lineages of carcinogenesis (different prostate lobes, mainly DLP and VP) in TRAMP mice after the lineage differences of the prostate carcinogenesis had been recognized [9,13]. For instance, Slack-Davis et al studied the requirement for focal adhesion kinase (FAK) signaling in cancer progression in TRAMP mice with C57BL/6 background [35]. They found that loss of FAK or its inhibition with PF-562271 (small molecular inhibitor for FAK) did not alter the progression to AHT.…”

Section: Molecular Changes In Prostate Carcinogenesis In Tramp Modelmentioning

confidence: 99%

Lobe-Specific Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) Mouse Model

Zhang¹,

Wang²,

Zhang³

et al. 2013

Carcinogenesis

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“…The activation of FAK and Akt has been reported to be closely associated with cell proliferation, anoikis resistance, migration, invasion and stemness of PC cells. [27][28][29][30][31][40][41][42] CXCR4 leads to the activation of diverse intracellular signaling pathways including the Akt pathway, 34,43,44 and CXCL12 evoked increased expression of FAK and enhanced FAK phosphorylation. 35 Furthermore, it has been established that the tumorigenic and metastatic process of PC is regulated by CXCL12/CXCR4 axis.…”

Section: Discussionmentioning

confidence: 99%

“…Among these pathways, the activation of FAK and Akt has been reported to be closely associated with cell proliferation, anoikis resistance, migration, invasion and stemness of PC cells. [27][28][29][30][31] In PC3-shTpl2 cells, depletion of Tpl2 led to a remarkable decrease in the phosphorylation levels of FAK and Akt, compared with those of control cells (Fig. 5a).…”

Section: Fak and Akt Mediate Oncogenic Effects Of Tpl2 In Adi Pc Cellsmentioning

confidence: 93%

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Tpl2 induces castration resistant prostate cancer progression and metastasis

Lee

Cho

Lee

et al. 2014

Intl Journal of Cancer

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Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.Prostate cancer (PC) is the most common cancer and second leading cause of cancer-related deaths in males in the United States. 1 Although androgen depletion therapy is highly effective in suppressing PC growth, persistent androgen ablation often results in the development of metastatic castration resistant prostate cancer (CRPC). 2 Currently, patients with metastatic CRPC are treated with taxane-based chemotherapeutic drugs. However, the treatment only serves as a palliative, and distant metastasis is the main cause of PC-related death. 3 Therefore, the identification of novel therapeutic targets in metastatic CRPC is the most urgent clinical requirement that remains unmet.Tumors contain a reservoir of cancer stem cells (CSCs) that are responsible for tumor initiation, progression, metastasis and therapeutic resistance. 4 Since emerging evidence suggests that PC CSCs represent the "bad seeds" of tumor, the molecular mechanisms that maintain PC CSCs could potentially serve as therapeutic targets for metastatic CRPC. 5,6 Although aldehyde dehydrogenase (ALDH) activity 7 and expression of CD44 8 and Bmi-1 9 have been suggested as specific PC CSC markers, using these markers as therapeutic targets is challenging because the molecules lack specific functional and/or enzymatic activities.Tumor progression locus 2 [Tpl2/MAP3 kinase 8 (MAP3K8)], a serine/threonine protein kinase, has been suggested to enhance tumor growth and metastatic progression in distinct types of human cancers. 10-12 Previously, we

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Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model

Cited by 46 publications

References 22 publications

β4 Integrin signaling induces expansion of prostate tumor progenitors

β4 Integrin signaling induces expansion of prostate tumor progenitors

Lobe-Specific Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) Mouse Model

Tpl2 induces castration resistant prostate cancer progression and metastasis

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