Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

Copland, John A.; Luxon, Bruce A.; Ajani, Laila; Maity, Tapati; Campagnaro, Erica; Guo, Hongqian; LeGrand, Shauna N.; Tamboli, Pheroze; Wood, Christopher G.

doi:10.1038/sj.onc.1206835

Cited by 100 publications

(90 citation statements)

References 40 publications

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“…We and others have determined that T␤RIII expression is lost or reduced in a broad spectrum of epithelialderived human cancers (17)(18)(19)(20)(21)35). Here, we uncover a biological function for T␤RIII in regulating cell migration by specifically suppressing directional persistence.…”

Section: Discussionmentioning

confidence: 92%

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

Mythreye¹,

Blobe

2009

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

127

139

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Loss of expression of the TGF-␤ superfamily coreceptor, the type III TGF-␤ receptor (T␤RIII or betaglycan), occurs in a broad spectrum of human cancers including breast, lung, ovarian, pancreatic, prostate, and renal cell cancer. T␤RIII suppresses cancer progression in vivo, at least in part, by reducing cancer cell motility. However, the mechanism by which T␤RIII regulates migration is unknown. Here, we demonstrate an unexpected TGF-␤ signaling independent role for T␤RIII in activating Cdc42, altering the actin cytoskeleton and reducing directional persistence to inhibit random migration of both cancer and normal epithelial cells. Functionally, T␤RIII through its interaction with the scaffolding protein ␤-arrestin2, activates Cdc42 and inhibits migration. These studies identify a TGF-␤ independent homeostatic function for T␤RIII in regulating cell migration.C ell migration is a complex process required for physiological functions including embryonic development and wound healing. Alterations in cell migration are also critical to disease pathogenesis, including inflammatory and vascular diseases, tumor cell invasion, and metastases (1, 2). The ability of cells to migrate is regulated both by the speed and the directionality of migration that can be triggered by external cues (i.e., chemotaxis) or because of the intrinsic property of cells to migrate (i.e., intrinsic persistence) that are in turn regulated by the Rho family of GTPases, integrins, the actin cytoskelton, and microtubules (3, 4). Several migratory processes in development and tissue remodeling occur without any evidence of extrinsic chemotactic signaling, relying instead on intrinsic cell migratory properties (5).The type III TGF-␤ receptor (T␤RIII/betaglycan), an 849 aa heparan sulfate proteoglycan, is the most abundant and ubiquitously expressed TGF-␤ superfamily coreceptor. T␤RIII has the potential to increase or decrease TGF-␤ signaling through mechanisms yet to be fully defined (6-8). T␤RIII is classically thought to function as a coreceptor, presenting TGF-␤ superfamily ligands to their respective signaling receptors (8). Recent studies have suggested essential, nonredundant roles for T␤RIII in regulating signaling through T␤RII and T␤RI as well as independently of T␤RII and T␤RI (9). T␤RIII null embryos die on embryonic day 13.5, exhibiting hepatic and cardiovascular defects (10). An essential role for T␤RIII has also been demonstrated in mesenchymal transformation during chick embryonic heart development (11, 12) and in mediating TGF-␤ resistance in intestinal goblet cells (13). We have defined essential roles for the cytoplasmic domain of T␤RIII in mediating TGF-␤ signaling independent of the ligand presentation role (14), along with regulating cell-surface levels of T␤RIII and T␤RII through interactions with G␣-interacting protein-interacting protein, C terminus (GIPC) (15) and ␤-arrestin2 (16).Loss of T␤RIII expression has been reported in multiple cancers, with loss of expression correlating with disease progression, advanced stage, or ...

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Section: Discussionmentioning

confidence: 92%

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

Mythreye¹,

Blobe

2009

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

127

139

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“…Additionally, the loss of T␤RIII has been associated with the development of renal cell carcinoma (31). Two recent reports have also suggested a tumor-suppressor role for T␤RIII in prostate cancer (9,32).…”

Section: Discussionmentioning

confidence: 99%

Modulation of NFκB Activity and E-cadherin by the Type III Transforming Growth Factor β Receptor Regulates Cell Growth and Motility

Criswell

Arteaga

2007

Journal of Biological Chemistry

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Transforming growth factor ␤ is growth-inhibitory in nontransformed epithelial cells but becomes growth-promoting during tumorigenesis. The role of the type I and II receptors in tumorigenesis has been extensively studied, but the role of the ubiquitously expressed type III receptor (T␤RIII) remains elusive. We developed short hairpin RNAs directed against T␤RIII to investigate the role of this receptor in breast cancer tumorigenesis. Nontumorigenic NMuMG mouse cells stably expressing short hairpin RNA specific to mouse T␤RIII (NM-kd) demonstrated increased cell growth, motility, and invasion as compared with control cells expressing shRNA to human T␤RIII (NM-con). Reconstitution of T␤RIII expression with rat T␤RIII abrogated the increased growth and motility seen in the NM-kd cells. In addition, the NM-kd cells exhibited marked reduction in the expression of the adherens junction protein, E-cadherin. This loss of E-cadherin was due to increased NFB activity that, in turn, resulted in increased expression of the transcriptional repressors of E-cadherin such as Snail, Slug, Twist, and Sip1. Finally, NMuMG cells in which T␤RIII had been knocked down formed invasive tumors in athymic nude mice, whereas the control cells did not. These data indicate that T␤RIII acts as a tumor suppressor in nontumorigenic mammary epithelial cells at least in part by inhibiting NFB-mediated repression of E-cadherin. The transforming growth factor (TGF)3 ␤s belong to a family of pleitropic cytokines that are involved in cell growth and proliferation, differentiation, deposition of extracellular matrix, and motility (1). The three TGF␤ isoforms (␤1, ␤2, and ␤3) bind to transmembrane receptor serine/threonine kinases. TGF␤1 and TGF␤3 can bind with high affinity to the TGF␤ type II receptor, resulting in activation of Smad 2/3 and downstream target genes. In contrast, TGF␤2 binds with low affinity to the type II receptor. The type III receptor (T␤RIII), or betaglycan, binds with high affinity to all three TGF␤ isoforms and is required for presenting TGF␤2 to the type II receptor (2).T␤RIII has been shown to play an essential role in the formation of the atrioventricular cushion in the development of the heart (3). Consistent with this observation, the T␤RIII null mouse is embryonically lethal because of heart and liver defects (4). The role for T␤RIII in cancer is less clear. Increased expression of TGF␤1 and all three TGF␤ receptors was found in higher grade lymphomas (5). Conversely, reduced expression of T␤RIII was found associated with advanced stage neuroblastomas and ovarian carcinomas (6, 7). Similarly, a recent report using cDNA microarrays demonstrated that low T␤RIII expression correlates with higher grade among a cohort of breast cancers (8). Additionally, overexpression of T␤RIII in MDA-231 human breast cancer cells and DU145 prostate cancer cells resulted in decreased tumor invasion in vitro and in vivo (9, 10). The reasons for this apparent contradictory role for T␤RIII in these different tumor types have not been elucidate...

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“…Normal renal cortex and primary tumor tissue were collected from each of five patients diagnosed with local disease (tumor-node-metastasis stage group I and II). Data were analyzed by two-dimensional ANOVA and hierarchical cluster, as described (31). Expression of sFRP1 was down-regulated in 15 of 15 patients tested, with Research.…”

Section: Resultsmentioning

confidence: 99%

Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma

Gumz¹,

Zou

Kreinest³

et al. 2007

Clinical Cancer Research

258

229

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Purpose: Incidence and mortality rates for renal cell carcinoma (RCC) have been rising for decades. Unfortunately, the molecular events that support RCC carcinogenesis remain poorly understood. In an effort to gain a better understanding of signaling events in clear cell RCC (cRCC), we investigated the antitumor activity of secreted frizzled-related protein 1 (sFRP1), a negative regulator of Wnt signaling. Experimental Design: Genomic profiling of cRCC tumors and patient-matched normal tissues was done and confirmed using quantitative PCR and immunohistochemistry. Methylation-specific PCR was done on patient samples to evaluate the mechanism responsible for sFRP1loss. sFRP1 expression was restored in cRCC cells and the effects on tumor phenotype were characterized. Results: Genomic profiling, quantitative PCR, and immunohistochemistry indicated that loss of sFRP1occurred in cRCC and papillary RCC patient tissues. Twelve Wnt-regulated genes were up-regulated in cRCC tissues, including c-myc and cyclin D1, potentiators of cell proliferation and survival. Methylation of the sFRP1 gene was one mechanism identified for attenuation of sFRP1 mRNA. Stable reexpression of sFRP1in cRCC cells resulted in decreased expression of Wnt target genes, decreased growth in cell culture, inhibition of anchorage-independent growth, and decreased tumor growth in athymic nude mice. Conclusions: To our knowledge, this is the first report to show that stable restoration of sFRP1 expression in cRCC cells attenuates the cRCC tumor phenotype. Our data support a role for sFRP1as a tumor suppressor in cRCC and that perhaps loss of sFRP1is an early, aberrant molecular event in renal cell carcinogenesis.

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Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

Cited by 100 publications

References 40 publications

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

Modulation of NFκB Activity and E-cadherin by the Type III Transforming Growth Factor β Receptor Regulates Cell Growth and Motility

Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma

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