Increased Transforming Growth Factor β1 Plasma Level in Patients with Renal Cell Carcinoma:A Tumor-Specific Marker?

Wunderlich, Heiko; Steiner, Thomas; Kosmehl, Hartwig; Junker, U.; Reinhold, Dirk; Reichelt, O.; Zermann, Dirk-Hendrik; Schubert, J.

doi:10.1159/000030255

Cited by 38 publications

(19 citation statements)

References 5 publications

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“…Fibrosis is not a common histologic finding in RCC. Thus, these two disease states present with elevated serum TGFb levels but are polar opposites, most likely due solely to differences in TBR expression that regulate sensitivity to TGFb (Wunderlich et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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Renal cell carcinoma (RCC) is a major health issue. Whereas localized disease can be cured surgically, there is no effective therapy for metastatic disease. The development of an effective therapy will require an understanding of the pathways that are important in RCC carcinogenesis and progression. Using genomic profiling of patientmatched tissue, we have identified aberrations in the transforming growth factor b (TGFb) signaling pathway in RCC. We observed loss of type III TGFb receptor (TBR3) expression in all RCC samples. This suggests that TBR3 loss is an early event in RCC carcinogenesis and plays a sentinel role in the acquisition of a tumorigenic phenotype. We also observed subsequent loss of type II TGFb receptor (TBR2) expression in metastatic RCCs. We propose that loss of TBR3 is necessary for RCC carcinogenesis, and that loss of TBR2 leads to acquisition of a metastatic phenotype. To this end, we have identified a human renal cell carcinoma line (UMRC6) that is representative of localized, nonmetastatic RCC, reflecting a loss of TBR3, but not TBR2 expression. Another cell line, UMRC3, is highly metastatic, having lost TBR3 and TBR2 expression. We demonstrate functional loss of TGFb responsiveness in these cell lines as observed through phenotypic and transcriptional responsiveness to exogenous TGFb. Restoring TBR2 and TBR3 expression in UMRC3 cells attenuates cell proliferation, completely restores TGFb-mediated transcriptional responses, and completely blocks anchorage independent-growth: while restoration of TBR2 partially restores TGFb-mediated signaling. Based on these data, we propose that dysregulation in TGFb signaling, through stepwise loss in receptor expression, plays a prominent role in RCC carcinogenesis and progression. In addition, these studies unequivocably demonstrate a link between loss of TBR3 and a human disease.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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“…Enhanced expression of TGF-␤ in the serum of renal cancer patients has been related to the development of RCC. 23,24 Inactivation of TGFBR2 coupled with insensitivity to inhibition by TGF-␤ has been confirmed in RCC. 11,25 Loss of expression of TGF-␤ receptors has been reported as a prognostic factor in patients with RCC.…”

Section: Somatic Alteration Of Tgfbr1 In Carcinomas Of the Human Kidnmentioning

confidence: 96%

An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder

Chen

Jackson

Costello

et al. 2004

Intl Journal of Cancer

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TGF-␤ signaling is frequently perturbed in many human cancers, including renal cell carcinomas (RCCs) and transitional cell carcinomas (TCCs) of the bladder. Genetic alterations of the TGF-␤ type 1 receptor (TGFBR1) may contribute to these perturbations. We therefore examined variations in the TGFBR1 gene by PCR, SSCP and RFLP in carcinomas of the urinary system and in tissues from noncancer, age-matched controls. A G3 A variant 24 bp downstream of the exon/intron 7 boundary of the TGFBR1 gene (Int7G24A) was evident in patients with RCC (46.5%, n ‫؍‬ 86) and bladder and upper urinary tract TCC (49.2%, n ‫؍‬ 65) significantly more frequently than in age-matched controls (28.3%, n ‫؍‬ 113, p < 0.002 by 2 test). Moreover, 8 homozygous variant carriers were found in the cancer groups, whereas not a single homozygous variant carrier was found in the control group. The Int7G24A allele (both heterozygous G/A and homozygous A/A carriers) was associated with increased RCC incidence (OR ‫؍‬ 2.20, 95% CI 1.22-3.96) and TCC incidence (OR ‫؍‬ 2.45, 95% CI 1.89 -3.16). One somatic mutation of serine to phenylalanine at codon 57 of the TG-FBR1 gene was confirmed in an upper urinary tract TCC. In conclusion, the Int7G24A variant in the TGFBR1 gene is significantly more frequent in patients with RCC and TCC than normal age-matched controls, suggesting that it may represent a risk factor for the development of kidney and bladder carcinomas. © 2004 Wiley-Liss, Inc. Key words: TGF-␤ type 1 receptor; renal cell carcinoma; bladder transitional cell carcinoma; upper urinary tract transitional cell carcinoma; genetic variant; SSCPCancer of the urinary system is among the 5 most frequent malignancies in the United States based on recent cancer statistics. 1 More than 7% of all cancers in 2004 will be cancers of the kidney or urinary bladder. RCCs, which kill nearly 35% of afflicted patients, account for the majority of kidney neoplasms. TCC of the bladder and upper urinary tract is the fourth most frequent malignancy in men. 1 Advances in the genetic understanding of renal neoplasms have been made through successful cloning and mutational screening of the VHL, TSC and MET proto-oncogenes. However, many sporadic RCCs lack evidence of involvement of these 3 genes. Thus, other genes involved in cell growth regulation may be associated with sporadic RCC. Acquisition of TGF-␤ resistance has been suggested to be an important progression factor in human RCC and bladder TCC. 2,3 Disruption of the TGF-␤ signaling pathway has been hypothesized as the predominant mechanism through which many types of tumor cells gain a selective growth advantage. 4 We focused on the TGFBR1 gene, an important component of the TGF-␤ signaling pathway, for genetic analysis in cancers of the kidney and urinary bladder.The TGF-␤ signal is transduced by 2 transmembrane serinethreonine kinase receptors. TGF-␤ binds first to TGFBR2 homodimers, which then form heterotetramers with 2 TGFBR1 molecules. As a consequence, the TGFBR2 kinase phosphorylates and activates TGFBR1. ...

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“…A number of hypotheses are generally offered, ranging from the simplistic notion that removal of a symptomatic local tumor may improve performance status and therefore improve prognosis, that reduction in tumor burden itself may enhance the potential of an immune-mediated response to systemic treatment, that removal of the tumor actually benefits the patient as a surrogate for removal of a source of growth factors, immunosuppressant cytokines, and other molecules that underlie paraneoplastic symptoms such as cachexia, and that nephrectomy removes a source of future additional metastases (10,27).…”

Section: The Era Of Cytokine Therapymentioning

confidence: 99%

Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma: Is It Still Imperative in the Era of Targeted Therapy?

Pantuck

Belldegrun

Figlin

2007

Clinical Cancer Research

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In the era before cytokine therapy, controversy existed about the need for cytoreductive nephrectomy in treating patients with metastatic renal cell carcinoma. In 1978, Dekernion showed that nephrectomy alone had no effect on survival. During this period, removal of the malignant kidney was confined to palliative therapy in some settings of metastatic RCC, such as pain related to the kidney mass, intractable hematuria, erythrocytosis, uncontrolled hypertension, or poorly controlled hypercalcemia.When interleukin-2 was approved by the Food and Drug Administration in 1992, the role of nephrectomy was reexamined. After a decade of controversy, two randomized controlled studies established that cytoreductive surgery has a role in properly selected patients and offers a survival advantage when done before cytokine therapy. Unfortunately, the mechanisms underlying this benefit remain poorly understood. Immunotherapy may work best when there is a small volume of cancer present, and removing a large primary tumor may prevent the seeding of additional metastases. Data have also suggested that primary tumors were capable of producing immunosuppressive compounds that might decrease the efficacy of immunotherapy. Another hypothesis suggested that removing the kidney altered the acid/base status of the patient to such an extent that the growth of the tumor was hindered. With the emergence in 2006 of two targeted agents for advanced renal cell carcinoma, the role of cytoreductive nephrectomy has reemerged as a source of controversy. Although evidence-based medical practice suggests a role for nephrectomy before the use of targeted agents, the arguments for and against this practice will be weighed.

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Increased Transforming Growth Factor β1 Plasma Level in Patients with Renal Cell Carcinoma:A Tumor-Specific Marker?

Cited by 38 publications

References 5 publications

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

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

An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder

Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma: Is It Still Imperative in the Era of Targeted Therapy?

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