IGF family members in renal cell carcinoma : their roles in malignancies and therapeutic interventions

Cheung, Catherine Wing Ying (2005). IGF family members in renal cell carcinoma : their roles in malignancies and therapeutic interventions PhD Thesis, University of Queensland. School of Medicine, The University of Queensland.

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Author Cheung, Catherine Wing Ying
Thesis Title IGF family members in renal cell carcinoma : their roles in malignancies and therapeutic interventions
School, Centre or Institute University of Queensland. School of Medicine
Institution The University of Queensland
Publication date 2005
Thesis type PhD Thesis
Supervisor Prof. David W. Johnson
A/Prof. David L Nicol
Total pages 345
Language eng
Subjects 111201 Cancer Cell Biology
111202 Cancer Diagnosis
Formatted abstract

Renal cell carcinoma (RCC) is a malignant renal neoplasm with a poor prognosis. The limited effective treatment options prompted further research into growth factors that regulate cellular proliferation, apoptosis and metastasis in RCC. In order to assess the physiological and pathological roles of members of the insulin-like growth factor family in RCC, the expression of these members in human RCC tissues and RCC cell lines, the biological functions of insulin-like growth factor (IGF) members in RCC regulation, and a potential therapeutic strategy to manipulate the levels of these members were examined. Using semi-quantitative PCR, human RCC tissues showed increased mRNA levels of IGF-1, IGFBP-3 and IGFBP-6 in clear cell RCC, decreased mRNA levels of IGF-1, IGFBP-4 and IGFBP-5 in papillary RCC, and decreased mRNA levels of IGFBP-2, IGFBP-4 and IGFBP-5 in benign oncocytomas. These changes were accompanied by concurrent alterations in the protein levels of certain IGFBPs, such as IGF-I and IGFBP-3 in clear cell RCC, as determined by semi-quantitative immunohistochemistry. Primary cultures of proximal tubular cells (priPTC) and renal cell carcinoma cells (priRCC), and a metastatic RCC cell line (SN12Kl), were characterised and found to demonstrate morphological and in vivo growth behaviour appropriate to their cellular identities. These cells also expressed mRNA and protein of IGF members similar to those found in normal kidney or RCC tissues. Stimulation of priPTC, priRCC, and SN12Kl cultures with exogenous IGF-I (100 ng/mL) increased DNA synthesis to different extents amongst various cell types. IGF-1-mediated DNA synthesis was specific to the IGF-1-signalling axis and was accompanied by upregulated IGFBP-3 levels in SN12Kl RCC cells. IGFBP-3 appeared to play a significant role in abrogating IOF-independent, and to a smaller extent, IGF-1-dependent growth   inhibition. As a therapeutic strategy to treat RCCs by antioxidants via manipulation of inhibitory IGFBP-3, silibinin was used to treat SN1 2Kl cell cultures and was orally fed to SCID mice orthotopically implanted with the cell line. In SN12Kl RCC cultures, silibinin inhibited DNA synthesis in a time- and dose-dependent manner at concentrations between 2.5 and 40 µmol/L. At these concentrations, cell viability was not significantly altered. For silibinin concentrations ≥80 µmol/L, the number of cells that underwent apoptosis or necrosis dramatically increased. This growth inhibition was found to be independent of IGFBP-3. A decrease of IGFBP-3 was found in SN12Kl upon silibinin treatment, a finding that contrasted with the initial hypothesis that increased IGFBP-3 was the direct mechanism for inhibiting tumour growth. In an in vivo mouse model of RCC, orally fed silibinin (0.4% in food pellets) suppressed tumour progression, as shown by dramatic decreases in tumour size and weight. Oral feeding with silibinin proved to be both a safe and effective means of targeting experimental RCC, although the mechanism and the role of IGFBBP-3 were not fully defined. The levels of plasma IGFBP-3 and tumour kidney IGFBP-3 mRNA were elevated at lower concentrations of silibinin tested (0.1% in food pellets). However, feeding of animals with higher concentrations of silibinin (0.2% and 0.4% in food pellet) resulted in decreased IGFBP-3 levels. The extents of proliferation and apoptosis (as determined by Ki-67 and caspase-3 markers) in the tumour-implanted kidneys were unaltered in any of the experimental groups.


In summary, members of the IGF family may be important in RCC progression. Members are differentially expressed in different histological subtypes of RCC, and between RCC and benign renal tumours. In particular, in vitro studies using RCC cultures demonstrate a stimulatory role for IGF-I and an inhibitory role for IGFBP-3. Although both in vitro and in vivo results for the anti-cancer effects of silibinin are encouraging, the exact mechanisms (including potential alteration of JGFBP-3 levels) remain uncertain.

Keyword Somatomedin -- Physiological effect
Insulin-like growth factor-binding proteins
Cancer cells
Kidneys -- Cancer

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Thu, 13 Jun 2013, 11:10:17 EST by Talha Alam on behalf of Scholarly Communication and Digitisation Service