The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer


  • Rehanna Mansor IGFs & Metabolic Endocrinology Group, School of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UK
  • Amit Bahl Department of Clinical Oncology, Bristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK
  • Jeff Holly IGFs & Metabolic Endocrinology Group, School of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UK
  • Claire M. Perks IGFs & Metabolic Endocrinology Group, School of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UK



Epithelial-to-mesenchymal transition, insulin-like growth factor family, prostate cancer progression, lifestyle factors.


 Prostate cancer is the second most common lethal cancer in men worldwide. Despite the fact that the prognosis for patients with localized disease is good, many patients succumb to metastatic disease with the development of resistance to hormone treatments. This is normally termed castration-resistant prostate cancer (CRPC). The development of metastatic, castration-resistant prostate cancer has been associated with epithelial-to-mesenchymal transition (EMT), a process where cancer cells acquire a more mesenchymal phenotype with enhanced migratory potential, invasiveness and elevated resistance to apoptosis. The main event in EMT is the repression of epithelial markers such as E-cadherin and upregulation of mesenchymal markers such as N-cadherin, vimentin and fibronectin. The insulin-like growth factor (IGF) signalling axis is essential for normal development and maintenance of tissues, including that of the prostate, and dysregulation of this pathway contributes to prostate cancer progression and malignant transformation. It is becoming increasingly clear that one of the ways in which the IGF axis impacts upon cancer progression is through promoting EMT. This review will explore the role of EMT in prostate cancer progression with a specific focus on the involvement of the IGF axis and its downstream signalling pathways in regulating EMT in prostate cancer.


Cancer Facts & Figures 2015 - acspc-044552.pdf [Internet]. [cited 2015 Sep 9].Available from: groups/content/@editorial/documents/document/acspc-044552.pdf

Prostate cancer statistics | Cancer Research UK [Internet]. [cited 2015 Sep 9]. Available from:

Baade PD, Youlden DR, Cramb SM, . Epidemiology of prostate cancer in the Asia-Pacific region. Prostate Int 2013; 1(2): 47-58.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65(1): 5-29.

Steinberg GD, Carter BS, Beaty TH, et al. Family history and the risk of prostate cancer. Prostate 1990; 17(4): 337-47.

Stanford JL, Ostrander EA. Familial prostate cancer. Epidemiol Rev 2001; 23(1): 19-23.

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 62(1): 10-29.

Allan CA, Collins VR, Frydenberg M, et al. Androgen deprivation therapy complications. Endocr Relat Cancer 2014; 21(4): T119-29.

Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10(1): 33-9.

Nguyen-Nielsen M, Liede A, Maegbaek ML, et al. Survival and PSA-markers for mortality and metastasis in nonmetastatic prostate cancer treated with androgen deprivation therapy. Cancer Epidemiol. Elsevier; 2015; 39(4): 623-32.

Taichman RS, Loberg RD, Mehra R, et al. The evolving biology and treatment of prostate cancer. J Clin Invest 2007; 117(9): 2351-61.

Malik R, Khan AP, Asangani IA, et al. Targeting the MLL complex in castration-resistant prostate cancer. Nat Med 2015; 21(4): 344-52.

Holly JMP, Zeng L, Perks CM. Epithelial cancers in the post-genomic era: should we reconsider our lifestyle? Cancer Metastasis Rev 2013; 32(3-4): 673-705.

Ito K. Prostate cancer in Asian men. Nat Rev Urol. Nature Publishing Group; 2014; 11(4): 197-212.

Key TJ, Schatzkin A, Willett WC, et al. Diet, nutrition and the prevention of cancer. Public Health Nutr 2007; 7(1a): 187-200.

Zhang J-Q, Geng H, Ma M, et al. Metabolic Syndrome Components are Associated with Increased Prostate Cancer Risk. Med Sci Monit 2015; 21: 2387-96.

Telli O, Sarici H, Ekici M, et al. Does metabolic syndrome or its components associate with prostate cancer when diagnosed on biopsy? Ther Adv Med Oncol 2015; 7(2): 63-7.

Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006; 15(11): 2056-62.

Liu X, Ji J, Sundquist K, et al. The impact of type 2 diabetes mellitus on cancer-specific survival: a follow-up study in Sweden. Cancer 2012; 118(5): 1353-61.

Xiang Y, Xiong H, Cui Z, et al. The association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence. J Exp Clin Cancer Res 2013; 32: 9.

Bitting RL, Schaeffer D, Somarelli JA, et al. The role of epithelial plasticity in prostate cancer dissemination and treatment resistance. Cancer Metastasis Rev 2014; 33(2-3): 441-68.

Sara VR, Hall K. Insulin-like growth factors and their binding proteins. Physiol Rev 1990; 70(3): 591-614.

Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16(1): 3-34.

Clemmons DR, Underwood LE. Nutritional Regulation of IGF-I and IGF Binding Proteins. Annu Rev Nutr 199; 11(1): 393-412.

Salmon WD, Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med 1957; 49(6): 825-36.

Ullrich A, Gray A, Tam AW, et al. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J 1986; 5(10): 2503-12.

LeRoith D, Werner H, Beitner-Johnson D, et al. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995; 16(2): 143-63.

Baker J, Liu JP, Robertson EJ, et al. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993; 75(1): 73-82.

Yamaguchi Y, Flier JS, Benecke H, et al. Ligand-binding properties of the two isoforms of the human insulin receptor. Endocrinology 1993; 132(3): 1132-8.

Wang C-F, Zhang G, Zhao L-J, et al. Overexpression of the insulin receptor isoform A promotes endometrial carcinoma cell growth. PLoS One 2013; 8(8): e69001.

Belfiore A, Frasca F, Pandini G, et al. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 2009; 30(6): 586-623.

Kelley KM, Oh Y, Gargosky SE, et al. Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol 1996; 28(6): 619-37.

Lin MZ, Marzec KA, Martin JL, et al. The role of insulin-like growth factor binding protein-3 in the breast cancer cell response to DNA-damaging agents. Oncogene 2014; 33(1): 85-96.

Terrien X, Bonvin E, Corroyer S, et al. Intracellular colocalization and interaction of IGF-binding protein-2 with the cyclin-dependent kinase inhibitor p21CIP1/WAF1 during growth inhibition. Biochem J 2005; 392(Pt 3): 457-65.

Liu B, Lee HY, Weinzimer SA, et al. Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-alpha regulate transcriptional signaling and apoptosis. J Biol Chem 2000; 275(43): 33607-13.

Perks CM, Holly JMP. IGF binding proteins (IGFBPs) and regulation of breast cancer biology. J Mammary Gland Biol Neoplasia 2008; 13(4): 455-69.

Baxter RC. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2014; 14(5): 329-41.

Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112(12): 1776-84.

Gravdal K, Halvorsen OJ, Haukaas SA, et al. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res 2007; 13(23): 7003-11.

Murali AK, Norris JS. Differential expression of epithelial and mesenchymal proteins in a panel of prostate cancer cell lines. J Urol. Elsevier; 2012; 188(2): 632-8.

Al Saleh S, Al Mulla F, Luqmani YA. Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. PLoS One 2011; 6(6): e20610.

Grant CM, Kyprianou N. Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression. Translational Andrology and Urology 2013. p 202-11.

Polette M, Mestdagt M, Bindels S, et al. Beta-catenin and ZO-1: shuttle molecules involved in tumor invasion-associated epithelial-mesenchymal transition processes. Cells Tissues Organs 2007; 185(1-3): 61-5.

Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J. EMBO Press; 2012; 31(12): 2714-36.

Vega S, Morales A V, Ocaña OH, et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004; 18(10): 1131-43.

Nisticò P, Bissell MJ, Radisky DC. Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol 2012; 4(2).

Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 2003; 3(5): 362-74.

Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119(6): 1420-8.

Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2(6): 442-54.

Tsai JH, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 2013; 27(20): 2192-206.

Zeisberg M, Neilson EG. Biomarkers for epithelial-mesen-chymal transitions. J Clin Invest 2009; 119(6): 1429-37.

Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006; 66(17): 8319-26.

Bonaldi CM, Azzalis LA, Junqueira VBC, et al. Plasma levels of E-cadherin and MMP-13 in prostate cancer patients: correlation with PSA, testosterone and pathological parameters. Tumori; 101(2): 185-8.

Kang Y, Massagué J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004; 118(3): 277-9.

Whiteland H, Spencer-Harty S, Thomas DH, et al. Putative prognostic epithelial-to-mesenchymal transition biomarkers for aggressive prostate cancer. Exp Mol Pathol 2013; 95(2): 220-6.

Tanaka H, Kono E, Tran CP, et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med 2010; 16(12): 1414-20.

Moustakas A, Heldin C-H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 2007; 98(10): 1512-20.

Jechlinger M, Grünert S, Beug H. Mechanisms in epithelial plasticity and metastasis: insights from 3D cultures and expression profiling. J Mammary Gland Biol Neoplasia 2002; 7(4): 415-32.

Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113(6): 685-700.

Niessen K, Fu Y, Chang L, et al. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol 2008; 182(2): 315-25.

Medici D, Hay ED, Olsen BR. Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. Mol Biol Cell 2008; 19(11): 4875-87.

Kokudo T, Suzuki Y, Yoshimatsu Y, et al. Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. J Cell Sci 2008; 121(Pt 20): 3317-24.

Massagué J. TGFbeta in Cancer. Cell 2008; 134(2): 215-30.

Sridurongrit S, Larsson J, Schwartz R, et al. Signaling via the Tgf-beta type I receptor Alk5 in heart development. Dev Biol 2008; 322(1): 208-18.

Nawshad A, Medici D, Liu C-C, et al. TGFbeta3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex. J Cell Sci 2007; 120(Pt 9): 1646-53.

Sarraj MA, Escalona RM, Umbers A, et al. Fetal testis dysgenesis and compromised Leydig cell function in Tgfbr3 (beta glycan) knockout mice. Biol Reprod 2010 ; 82(1): 153-62.

Giampieri S, Manning C, Hooper S, et al. Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 2009; 11(11): 1287-96.

Siegel PM, Shu W, Cardiff RD, et al. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 2003; 100(14): 8430-5.

Pu H, Collazo J, Jones E, et al. Dysfunctional transforming growth factor-beta receptor II accelerates prostate tumorigenesis in the TRAMP mouse model. Cancer Res 2009; 69(18): 7366-74.

Yang F, Tuxhorn JA, Ressler SJ, et al. Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. Cancer Res 2005; 65(19): 8887-95.

McCaig C, Fowler CA, Laurence NJ, et al. Differential interactions between IGFBP-3 and transforming growth factor-beta (TGF-beta) in normal vs cancerous breast epithelial cells. Br J Cancer 2002; 86(12): 1963-9.

Chen X-H, Liu Z-C, Zhang G, et al. TGF-β and EGF induced HLA-I downregulation is associated with epithelial-mesenchymal transition (EMT) through upregulation of snail in prostate cancer cells. Mol Immunol 2015; 65(1): 34-42.

Siu MK, Tsai Y-C, Chang Y-S, et al. Transforming growth factor-β promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway. Oncogene 2015; 34(36): 4767-76.

Blanco MJ, Moreno-Bueno G, Sarrio D, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 2002; 21(20): 3241-6.

Dhanasekaran SM, Barrette TR, Ghosh D, et al. Delineation of prognostic biomarkers in prostate cancer. Nature 2001; 412(6849): 822-6.

Beach S, Tang H, Park S, et al. Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Oncogene 2008; 27(15): 2243-8.

Poblete CE, Fulla J, Gallardo M, et al. Increased SNAIL expression and low syndecan levels are associated with high Gleason grade in prostate cancer. Int J Oncol 2014; 44(3): 647-54.

Odero-Marah VA, Wang R, Chu G, et al. Receptor activator of NF-kappaB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells. Cell Res 2008; 18(8): 858-70.

Wen Y-C, Lee W-J, Tan P, et al. By inhibiting snail signaling and miR-23a-3p, osthole suppresses the EMT-mediated metastatic ability in prostate cancer. Oncotarget. Impact Journals; 2015. p. 21120-36.

McKeithen D, Graham T, Chung LWK, et al. Snail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells. Prostate 2010; 70(9): 982-92.

Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117(7): 927-39.

Galván JA, Zlobec I, Wartenberg M, et al. Expression of E-cadherin repressors SNAIL, ZEB1 and ZEB2 by tumour and stromal cells influences tumour-budding phenotype and suggests heterogeneity of stromal cells in pancreatic cancer. Br J Cancer 2015; 112(12): 1944-50.

Liu A, Zhu Z-H, Chang S, et al. Twist expression associated with the epithelial-mesenchymal transition in gastric cancer. Mol Cell Biochem 2012; 367(1-2): 195-203.

Alexander NR, Tran NL, Rekapally H, et al. N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res 2006; 66(7): 3365-9.

Shiota M, Zardan A, Takeuchi A, et al. Clusterin mediates TGF-β-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Res 2012; 72(20): 5261-72.

Marchini S, Fruscio R, Clivio L, et al. Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer. Eur J Cancer 2013; 49(2): 520-30.

Witta SE. Restoring E-Cadherin Expression Increases Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cell Lines. Cancer Res 2006; 66(2): 944-50.

Holder AM, Akcakanat A, Adkins F, et al. Epithelial to mesenchymal transition is associated with rapamycin resistance. Oncotarget. Impact Journals; 2015. p 19500-13.

Pavese JM, Bergan RC. Circulating tumor cells exhibit a biologically aggressive cancer phenotype accompanied by selective resistance to chemotherapy. Cancer Lett 2014; 352(2): 179-86.

Marín-Aguilera M, Codony-Servat J, Reig Ò, et al. Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mol Cancer Ther 2014; 13(5): 1270-84.

Baritaki S, Yeung K, Palladino M, et al. Pivotal roles of snail inhibition and RKIP induction by the proteasome inhibitor NPI-0052 in tumor cell chemoimmunosensitization. Cancer Res 2009; 69(21): 8376-85.

Schernhammer ES, Holly JM, Pollak MN, et al. Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2005; 14(3): 699-704.

Erarslan E, Coşkun Y, Türkay C, et al. IGF-I levels and visceral fat accumulation in colonic neoplasia. Clin Res Hepatol Gastroenterol 2014; 38(1): 99-105.

Schaffer A, Koushik A, Trottier H, et al. Insulin-like growth factor-I and risk of high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 2007; 16(4): 716-22.

Cao Y, Nimptsch K, Shui IM, et al. Prediagnostic plasma IGFBP-1, IGF-1 and risk of prostate cancer. Int J Cancer 2015; 136(10): 2418-26.

Renehan AG, Zwahlen M, Minder C, et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet (London, England) 2004; 363(9418): 1346-53.

Harman SM, Metter EJ, Blackman MR, et al. Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical pro-state cancer. J Clin Endocrinol Metab 2000; 85(11): 4258-65.

Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998; 279(5350): 563-6.

Rowlands M-A, Holly JMP, Hamdy F, et al. Serum insulin-like growth factors and mortality in localised and advanced clinically detected prostate cancer. Cancer Causes Control 2012; 23(2): 347-54.

Biernacka KM, Perks CM, Holly JMP. Role of the IGF axis in prostate cancer. Minerva Endocrinol 2012; 37(2): 173-85.




How to Cite

Rehanna Mansor, Amit Bahl, Jeff Holly, & Claire M. Perks. (2015). The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer. Journal of Analytical Oncology, 4(4),  157–170.