Abstract
Enhanced angiogenesis and perineural invasion are markers of poor prognosis in patients with pancreatic cancer. Systemic therapies for pancreatic cancer have been largely ineffective, and thus improved, targeted therapies are needed. Single nucleotide polymorphisms (SNP) are DNA sequence variations that result in vast diversity of disease susceptibility and response to disease. CXCR2 is an important mediator of CXC chemokine-induced angiogenesis and is upregulated in pancreatic cancer. In a preclinical corneal micropocket assay, treatment of pancreatic cancer cell lines that express CXCR2 with anti-CXCR2 antibody inhibited angiogenesis. To date, there have not been any CXCR2 SNP associated with pancreatic cancer, but CXCR2 SNP has been postulated to be associated with angiogenesis in systemic sclerosis. The receptor tyrosine kinase encoded by the RET gene and its ligand glial derived neurotrophic factor (GDNF) are upregulated in pancreatic cancer. In vitro treatment of pancreatic cancer cell lines that express RET with anti-RET antibody or RET siRNA-inhibited GDNF-induced invasiveness. G691S RET SNP has been previously shown to be associated with enhanced pancreatic cancer invasiveness. We suggest that molecular profiling of each patient’s tumor for G691S RET SNP, potentially CXCR2 SNP, and also other yet-to-be identified SNP associated with pancreatic cancer will allow for both improved understanding of individual prognosis and allow for utilization of more personalized, targeted adjuvant therapies.
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References
Sachidanandam R, Weissman D, Schmidt SC et al (2001) A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409:928–933
Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM (2007) Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res 67:9609–9612
Dong LM, Potter JD, White E et al (2008) Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. JAMA 299:2423–2436
Kuehn R, Lelkes PI, Bloechle C et al (1999) Angiogenesis, angiogenic growth factors, and cell adhesion molecules are upregulated in chronic pancreatic diseases: angiogenesis in chronic pancreatitis and in pancreatic cancer. Pancreas 18:96–103
Karademir S, Sokmen S, Terzi C et al (2000) Tumor angiogenesis as a prognostic predictor in pancreatic cancer. J Hepatobiliary Pancreat Surg 7:489–495
Fujioka S, Yoshida K, Yanagisawa S et al (2001) Angiogenesis in pancreatic carcinoma: thymidine phosphorylase expression in stromal cells and intratumoral microvessel density as independent predictors of overall and relapse-free survival. Cancer 92:1788–1797
Buchler P, Reber HA, Buchler MW et al (2002) VEGF-RII influences the prognosis of pancreatic cancer. Ann Surg 236:738–749
Kindler HL, Friberg G, Singh DA et al (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033–8040
Sunamura M, Duda DG, Ghattas MH et al (2003) Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer. Angiogenesis 6:15–24
Kasper HU, Ebert M, Malfertheiner P et al (2001) Expression of thrombospondin-1 in pancreatic carcinoma: correlation with microvessel density. Virchows Arch 438:116–120
Wente MN, Keane MP, Burdick MD et al (2006) Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cell-induced angiogenesis. Cancer Lett 241:221–227
Strieter RM (2005) Masters of angiogenesis. Nat Med 11:925–927
Semenza G (2002) Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 64:993–998
Semenza GL (2001) Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7:345–350
Cramer T, Yamanishi Y, Clausen BE et al (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657
Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288
Nakanishi C, Toi M (2005) Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 5:297–309
Richmond A (2002) Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol 2:664–674
Baggiolini M, Walz A, Kunkel SL (1998) Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest 84:1045–1049
Matsushima K, Oppenheim JJ (1998) Interleukin 8 and MCAF: novel inflammatory cytokines inducible by IL 1 and TNF. Cytokine 1:2–13
Miller MD, Krangel MS (1992) Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines. Crit Rev Immunol 12:17–46
Oppenheim JJ, Zachariae CO, Mukaida N, Matsushima K (1991) Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu Rev Immunol 9:617–648
Farber JM (1993) HuMig: a new human member of the chemokine family of cytokines. Biochem Biophys Res Commun 192:223–230
Proost P, De Wolf-Peeters C, Conings R et al (1993) Identification of a novel granulocyte chemotactic protein (GCP-2) from human tumor cells. In vitro and in vivo comparison with natural forms of GRO, IP-10, and IL-8. J Immunol 150:1000–1010
Walz A, Burgener R, Car B et al (1991) Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin 8. J Exp Med 174:1355–1362
Strieter RM, Polverini PJ, Kunkel SL et al (2001) The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 270:27348–27357
Arenberg DA, Kunkel SL, Polverini PJ et al (1996) Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 97:2792–2802
Arenberg DA, Keane MP, DiGiovine B et al (1998) Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin Invest 102:465–472
Luan J, Shattuck-Brandt R, Haghnegahdar H et al (1997) Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression. J Leukoc Biol 62:588–597
Arenberg DA, Kunkel SL, Polverini PJ et al (1996) Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. J Exp Med 184:981–992
Addison CL, Arenberg DA, Morris SB et al (2000) The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis. Hum Gene Ther 11:247–261
Strieter RM, Kunkel SL, Arenberg DA et al (1995) Interferon gamma-inducible protein 10 (IP-10), a member of the C-X-C chemokine family, is an inhibitor of angiogenesis. Biochem Biophys Res Commun 210:51–57
Addison CL, Daniel TO, Burdick MD et al (2000) The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR + CXC chemokine-induced angiogenic activity. J Immunol 165:5269–5277
Murphy PM (1994) The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol 12:593–633
Le X, Shi Q, Wang B et al (2000) Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma. J Interferon Cytokine Res 20:935–946
Shi Q, Abbruzzese JL, Huang S et al (1999) Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 5:3711–3721
Shi Q, Le X, Abbruzzese JL et al (1999) Cooperation between transcription factor AP-1 and NF-kappaB in the induction of interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia. J Interferon Cytokine Res 19:1363–1371
Gupta M, Song P, Yates CR, Meibohm B (2004) Real-time PCR-based genotyping assay for CXCR2 polymorphisms. Clin Chim Acta 341:93–100
Yang HP, Woodson K, Taylor PR et al (2006) Genetic variation in interleukin 8 and its receptor genes and its influence on the risk and prognosis of prostate cancer among Finnish men in a large cancer prevention trial. Eur J Cancer Prev 15:249–253
Renzoni E, Lympany P, Sestini P et al (2000) Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum 43:1633–1640
Viana AC, Kim YJ, Cirelli JA et al (2007) A novel PCR-RFLP assay for the detection of the single nucleotide polymorphism at position +1440 in the human CXCR2 gene. Biochem Genet 45:737–741
Lin LF, Doherty DH, Lile JD et al (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132
Airaksinen MS, Saarma M (2002) The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3:383–394
Ketterer K, Rao S, Friess H et al (2003) Reverse transcription-PCR analysis of laser-captured cells points to potential paracrine and autocrine actions of neurotrophins in pancreatic cancer. Clin Cancer Res 9:5127–5136
Sakamoto Y, Kitajima Y, Edakuni G et al (2001) Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma. Oncol Rep 8:477–484
Sawai H, Okada Y, Kazanjian K et al (2005) The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res 65:11536–11544
Ito Y, Okada Y, Sato M et al (2005) Expression of glial cell line-derived neurotrophic factor family members and their receptors in pancreatic cancers. Surgery 138:788–794
Kodama Y, Asai N, Kawai K et al (2005) The RET proto-oncogene: a molecular therapeutic target in thyroid cancer. Cancer Sci 96:143–148
Takahashi M, Ritz J, Cooper GM (1985) Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42:581–588
Eng C (1999) RET proto-oncogene in the development of human cancer. J Clin Oncol 17:380–393
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Donahue, T.R., Hines, O.J. CXCR2 and RET Single Nucleotide Polymorphisms in Pancreatic Cancer. World J Surg 33, 710–715 (2009). https://doi.org/10.1007/s00268-008-9826-z
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DOI: https://doi.org/10.1007/s00268-008-9826-z