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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 1  |  Page : 69-74
Prognostic value of insulin- like growth factor-I receptor expression in renal cell carcinoma


1 Department of Urology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of English, School of Humanities, Yazd University, Yazd, Iran

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Date of Web Publication8-Jan-2010
 

   Abstract 

The Insulin-Like growth factor-I receptor (IGF-IR), a tyrosine-kinas receptor over expressed in many tumor cell lines and in some human tumors, plays a critical role in trans苯ormation, tumorigenicity and metastasis. The aim of the present study is to investigate the role of IGF-IR expression as a prognostic factor in RCC. This study was conducted in a historical cohort of 82 patients who had RCC treated with radical nephrectomy from 1994 to 2005. Specimens were reevaluated with regard to histological subtype, nuclear grade, stage and IGF-IR expression. The IGF-IR stain was semi- quantitatively evaluated using the Allred score system. Kaplan-Meier analysis demonstrated a significant positive correlation between Fuhrman nuclear grade and IGF背R Allred score (P< 0.0001). Survival in patients with score IGF-I ≤ 4 was 90.21 month and in patients with score IGF-1R> 4 was 33.39 month (P Value < 0.0001). Cox regression analysis in苓icated that expression of IGF-IR is a prognostic factor in patients with RCC (P Value < 0.0001, odds Ratio = 2.38). In conclusion, a statistically significant correlation was demonstrated between IGF-IR expression and Fuhrman nuclear grading and survival in patients with RCC. In stage-by貞tage and grade-by-grade analysis; however, it seems that we cannot consider IGF-IR as an inde計endent prognostic factor.

How to cite this article:
Sichani MM, Yazdi FS, Moghaddam NA, Chehrei A, Kabiri M, Naeimi A, Taheri D. Prognostic value of insulin- like growth factor-I receptor expression in renal cell carcinoma. Saudi J Kidney Dis Transpl 2010;21:69-74

How to cite this URL:
Sichani MM, Yazdi FS, Moghaddam NA, Chehrei A, Kabiri M, Naeimi A, Taheri D. Prognostic value of insulin- like growth factor-I receptor expression in renal cell carcinoma. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 May 29];21:69-74. Available from: http://www.sjkdt.org/text.asp?2010/21/1/69/58713

   Introduction Top


Renal cell carcinoma is the most common re要al cancer and represents approximately 60 to 70% of all renal tumors in adults. [1] RCC encom計asses several clinically and pathologically dis負inct subtypes. More than 85% of RCCs are classified as clear cell carcinomas (CC-RCC).

The overall incidence and mortality of RCC is steadily increasing for reasons not fully ex計lained. [2] Currently, tumor stage and grade are considered as the only widely accepted prog要ostic indicators of RCC. As such, there is a need to identify other prognostic markers be苞ause the behavior of RCC cannot always be determined by stage alone. [3]

Recent studies on RCC have mainly focused on identifying the molecular prognostic factor, including growth factor [4],[5] and oncogenes. [6],[7] In sulin-Like Growth Factors (IGFs) are candidate proliferation markers in RCC due to their over苔ll importance in embryogenesis (renal growth and development); and somatic growth, diffe訃entiation, and tumor genesis. [8],[9],[10],[11] Although IGFs are mainly produced from the liver, their auto苞rine and paracrine activities are observed in most tissues. [12],[13]

Most of the biological activities of IGFS are mediated through Insulin-Like growth factor-1 receptor (IGF-IR). [14] The present study aims at investigating the role of IGF-IR expression as a prognostic factor in RCC.


   Materials and Methods Top


This historical cohort study was conducted in Alzahra Hospital on 82 patients with non me負astatic renal cell carcinoma who were treated with Radical Nephrectomy between 1994 and 2005. Paraffin embedded specimens were cho貞en, 31 cases were excluded from the study be苞ause of incomplete information, patients' non苞ompliance for the follow-up investigation or loss of paraffin block.

All specimens were reevaluated with regard to histological subtype, nuclear grade and stage by two pathologists. Nuclear grade was assigned using Fuhrman classification, [15] and the patholo茆ical stage was adjusted according to the TNM staging system.

Follow-up studies were performed at the uro衍ogy department of the hospital. The routine follow-up regimens for T 1 tumors were his負ory, physical examination and liver function test yearly; for T 2 tumors they were history, physical examination, liver function tests, CXR and abdominal ultrasonography yearly; for T 3 tumors they were history, physical examination, liver function test and CXR every 6 months for 3 years and then yearly and abdominal ultraso要ography at the first year and then yearly.

Immunohistochemistry (IHC)

Anti- IGF-IR monoclonal antibody was applied to 5 μm section from formalin-fixed paraffin-embedded tissue specimens, using the envision + Detection system/DAB + . Paraffin sections were deparaffinized with Xylen and dehydra負ed through graduated alcohols up to 70%, slides were incubated with antibody at a dilution of 1:50, using antibody Diluent's for 20 minutes at room temperature. Having been washed with PBS (PH=7.2), the slides were then incubated with labeled polymer HRP for 30 minutes.

The stain was semi quantitatively examined by 2 pathologists using the Allred 8- unit sys負em with the combination of a proportion score from 0 to 5 and an intensity score from 0 to 3 for each tumor, the tumor epithelial cells pro計ortion score and intensity score was deter衫ined.

The proportion score included the practice of positively stained tumor cells as follows:

0, none; 1: < 1/100; 2: 1/100 to 1/10; 3: 1/10 to 1/3; 4: 1/3 to2/3; 5 :>2/3.

The estimated average staining intensity of the positive tumor cells was expressed as fo衍lows, 0, none; 1, weak; 2, intermediate; 3, strong. In all cases, the adjacent normal paren苞hyma demonstrated strong IGF-IR immuno貞taining [Figure 1]. For survival Analysis, the patients were divided into two groups: the former with IGF-IR ≤ 4 and the latter with IGF-IR >4.


   Statistical Analysis Top


The data was analyzed via SPSS (SPSS Inc, Chicago IL, USA, version 15). Simple descrip負ive techniques were used to describe the va訃iables amongst the participants. Overall survi赳al of patients with RCC was determined with life table method. Survival of patients with and without IGF-IR expression was evaluated by Kaplan- Meier method and compared by the Log-Rank test, and then multi variants analysis was done with Cox regression. Chi square test was used to show the relationship between quantitative data. The level of significance was 0.05.


   Results Top


During a maximum 12 years of follow-up study of 82 patients, 31 were excluded. [Table 1] shows the patients' characteristics in this study; Cases of Fuhrman nuclear grade I had a mean overall score IGF-IR 1.9 (1.14 to 2.6), grade II 3.7 (3.1 to 4.3), grade III 7.1 (6.9 to 7.3) [Figure 2], grade IV 8 (8 0); which were statistically significant (P< 0.0001); The IGF背R immunostaining Allred 8-unit system score enhanced as the Fuhrman nuclear grade of tu衫or increased.

[Table 2] shows the life table of overall sur赳ival RCC cases; The 5 year's total survival of patient was 68.07%. Mean of survival time in patients who had tumors with IGF-IR ≤ 4 Expression was 90.21 (81.18 to 99.25) and who had tumors with IGF-IR > 4 expression was 33.39 month (21.21-45.58) (P< 0.0001) [Figure 3].

According to the Results of Cox Regression analysis, IGF-IR score seems to be a prognos負ic factor (P value < 0.0001, odds ratio 2:38). In the Step-Wise-Cox Regression analysis when compared grade by grade and stage by stage, apparently we cannot consider IGF-R as an in苓ependent prognostic factor. Based on the Cox proportional hazard model that adjusted stage and grade, patients with tumors that exhibited IGF-IR > 4 had a death risk more than patients with IGF-IR ≤ 4 [Figure 4].


   Discussion Top


Currently, tumor stage and grade are consi苓ered as the only widely accepted prognostic indicators of CC-RCC. There is a need to iden負ify other prognostic markers since the behavior of CC-RCC cannot always be determined by stage alone.

Recent studies on RCC have mainly focused on identifying molecular prognostic factors. [16] Insulin-like growth factors (IGF S ) are candidate proliferation markers in RCC. Most of the bio衍ogical activities of IGFS are mediated through IGF-IR. [17]

Nazeel Ahmad et al in 2004 showed a signi苯icant positive correlation between Fuhrman nuclear grade of RCC and IGF-IR Allred Score. [18] Alexander S. Parker et al in 2003 showed that patients with IGF-IR positive CC- RCC experienced significantly decreased cancer specific survival than those with IGF-IR ne茆ative cases. The risk of CC-RCC death asso苞iated with IGF-IR expression was strongest amongst the patients with earlier stage disease (T 1 and T 2 ). [19] Parker et al in 2002 demonstrated a correlation between the IGF-IR expression and the nuclear grade in white post menopau貞al females and suggested that IGF-IR may be a prognostic indicator of cancer-specific survi赳al amongst female patients with CC-RCC. [16] Alexander S. Parker et al in 2004 found some evidence to support a relationship between IGF1R expression and survival in patients with T 1 CC-RCC, especially amongst those with high茆rade tumors. [3] Schips et al. in 2004 showed that expression of IGF-Iand IGF-IR was not rela負ed to tumor stage, grade or prognosis. [20]

In conclusion, the present study has demons負rated a statistically significant correlation bet趴een IGF-IR expression and Fuhrman nuc衍ear grading and survival in patients with RCC. In stage-by-stage and grade-by-grade analysis; however, it seems that we cannot consider IGF背R as an independent prognostic factor. In this respect, more extensive studies examining the survival of CC-RCC patients' and its relation to IGF-IR expression.

 
   References Top

1.Reater VE, Gaadin PB. Adult renal tumors, in sternbergs D (ed). Diagnostic surgical pathology, 3th ed. Philadelphia, PA, Lippincott Williams& Wilkins, USA. 1999:1955-8.  Back to cited text no. 1      
2.Chow WH, Devesa SS, Fraumeni JF Jr. Epide衫iology of renal carcinoma. In: Comprehensive textbook of genitourinary oncology. 2nd ed. Edited by Vogelzang NJ, Shipley WU, Scardino PT, Coffey DS. Philadelphia: Lippincott, Williams and Wilkins. 2000:101-10.  Back to cited text no. 2      
3.Parker AS, Cheville JC, Blute ML, Igel T, Lohse CM, Cerhan JR. Pathologic T1 clear cell Renal cell carcinoma: Insulin like growth factor-I Receptor expression and disease范pecific survival. J Urol 2004;42:2577-82.  Back to cited text no. 3      
4.Uhlman D, Nguyen P, Manivel JC, et al. Epi苓ermal growth factor receptor and transfor衫ing growth factor alpha expression in papi衍lary and non papillary renal cell carcinoma; correlation with metastatic behavior and prognosis. Clin Cancer Res 1995;1:913-20.  Back to cited text no. 4      
5.Horie S, Tobisu KI, Fujimoto H, Doi N, Kakizoe T. Urinary incontinence after non nerve-sparing radical prostatectomy with no adjuvant andro茆en deprivation. Urology 1999;53:561-7.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.LI JJ, Hou X, Banerjee SK, Liao DZ, Maggouta F, Norris JS. Overexprossion and amplification of C-myc in the Syrian hamster kidney during estrogen carcinogenesis: a probable critical role in neoplastic transformation. Cancer Res 1999:53:561-7.  Back to cited text no. 6      
7.Clifford SC, Czapla K, Richards FM, O'Dono茆hue DJ, Maher ER. Hepatocyte growth factor貞timulated renal tubular mutagenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes. Br J Cancer 1998;77:1420-8.  Back to cited text no. 7      
8.Osgerby JC, Gadd TS, Wathes DC. Expression of insulin like growth factor binding protein-1 (IGF-BP-1) mRNA in the ovine uterus through觔ut the oestrous cycle and early pregnancy. J Endocrinol 1999;162:279-87.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Morison IM, Becroft DM, Taniguchi T, Woods CG, Reeve AE. Nat. Somatic overgrowth asso苞iated with overexpression of insulin-like growth factor II. Medicine 1996;2:311-6.  Back to cited text no. 9      
10.Rogers SA, Powell-Braxton L, Hammerman MR. Insulin- Like growth factor I regulates renal development in rodents. Dev Genet 1999;24: 293-8.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Hammerman MR, Miller SB. Effects of growth Hormone and insuline like growth factor 1 on renal growth and function. J Pediatr 1997:131: 17-9.  Back to cited text no. 11      
12.Simmons JG, Pucilowska JB, Lund PK. Auto苞rine and paracrine actions of intestinal fibroblast苓erived insulin-like growth factors. Am J Physiol 1999;279:817-27.  Back to cited text no. 12      
13.Manousos O, Souglakos J, Bosetti C, Tzonou A, Chatzidakis V, Trichopoulos D. IGF-I and IGF-II in relation to colorectal cancer. Int J Cancer 1999;83:15-7.  Back to cited text no. 13      
14.Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosin kinase activity. J Cell 1990;61:203-12.  Back to cited text no. 14      
15.Letourneux H, Lindner V, Lang H, et al. Repro苓ucibility of Fuhrman nuclear grade: advan負ages of a two-grade system. Prog Urol 2006; 16(3):281-5.  Back to cited text no. 15      
16.Parker AS, Cheville J, Jonney CA, Cerhan J. High expression level of insulin-like growth factor-1 receptor predict poor survival among woman with clear-cell renal cell carcinoma. Hum Pathol 2002;33:801-5.  Back to cited text no. 16      
17.Datta K, Nambudripad R, Pal S, Zhou M, Cohn HT, Mukhopadhay D. Inhibition of insulin-like growth factor-I- mediated cell signaling by the von Hipple-lindau Gene product in renal cancer. J Biol 2000;275:20700-6.  Back to cited text no. 17      
18.Ahmad N, Keehn CA, Coppola D. The expre貞sion of Insulin-Like growth factor-I receptor correlates with Fuhrman grading of renal cell carcinoma. Hum Pathol 2004;35: 1132-6.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]  
19.Parkor AS, Cheville JC, Lohse C, Cerham JR, Blute ML. Expression of Insulin- Like growth factor I receptor and survival in patients with clear cell renal cell carcinoma. J Urol 2003; 170:420-4.  Back to cited text no. 19      
20.Schips L, Zigeaner R, Ratschek M, Rehak P, Ruschoff J, Languer C. Analysis of insulin衍ike growth factors and insulin-like growth factor I receptor expression in renal cell carci要oma. Am J Clin Pathol 2004;122(6):931-7.  Back to cited text no. 20      

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Correspondence Address:
Diana Taheri
Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan
Iran
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