Abstract
Background: There is a paucity of known molecular markers that distinguish pancreatic neuroendocrine tumors from other pancreatic tumor types. We hypothesized that novel markers for pancreatic neuroendocrine tumors could be identified with molecular fingerprinting of pooled RNA samples from core biopsies.
Methods: Total RNA was harvested from nine core biopsies of normal pancreas, pancreatitis, pancreatic adenocarcinoma, pancreatic adenocarcinoma metastases, and pancreatic neuroendocrine tumors. RNA from each group of samples was pooled and hybridized to an oligonucleotide-based microarray. Four genes (ANG2, NPDC1, ELOVL4, and CALCR) were selected for further investigation by reverse transcriptase polymerase chain reaction from the top 20 highest expressed genes, on the basis of potential as novel markers.
Results: Neuroendocrine tumors were most unique from normal pancreas. Pancreatitis, pancreatic adenocarcinoma, and metastases are more closely related to each other and to normal pancreas. ANG2 was overexpressed in 89% of neuroendocrine tumors, compared with 22% of normal pancreas, making it the best potential molecular marker or therapeutic target of the four genes selected for analysis.
Conclusion: We have identified a specific set of molecular markers for pancreatic neuroendocrine tumors distinct from pancreatitis and pancreatic adenocarcinoma. These novel markers may prove useful as molecular markers or therapeutic targets unique to pancreatic neuroendocrine tumors.
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REFERENCES
Azimuddin K, Chamberlain RS. The surgical management of pancreatic neuroendocrine tumors. Surg Clin North Am 2001; 81: 511–25.
Kent RB 3rd, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg 1981; 193: 185–90.
Alexander H, Jensen R. Pancreatic endocrine tumors. In: DeVita V Jr, Hellman S, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott, Williams & Wilkins, 2001: 1788–813.
Yao KA, Talamonti MS, Nemcek A, et al. Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. Surgery 2001; 130: 677–82;discussion, 682–5.
Que FG, Nagorney DM, Batts KP, et al. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg 1995; 169: 36–42;discussion, 42–3.
Sarmiento JM, Que FG, Grant CS, et al. Concurrent resections of pancreatic islet cell cancers with synchronous hepatic metastases: outcomes of an aggressive approach. Surgery 2002; 132: 976–82;discussion, 982–3.
Ramsay G. DNA chips: state-of-the art. Nat Biotechnol 1998; 16: 40–4.
DeRisi J, Penland L, Brown PO, et al. Use of a cDNA microarray to analyze gene expression patterns in human cancer. Nat Genet 1996; 14: 457–60.
Agrawal D, Chen T, Irby R, et al. Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling. J Natl Cancer Inst 2002; 94: 513–21.
Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998; 11: 155–68.
Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 1996; 87: 1161–9.
Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277: 55–60.
Colen KL, Crisera CA, Rose MI, et al. Vascular development in the mouse embryonic pancreas and lung. J Pediatr Surg 1999; 34: 781–5.
Tanaka S, Mori M, Sakamoto Y, et al. Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. J Clin Invest 1999; 103: 341–5.
Tanaka F, Ishikawa S, Yanagihara K, et al. Expression of angiopoietins and its clinical significance in non-small cell lung cancer. Cancer Res 2002; 62: 7124–9.
Galiana E, Vernier P, Dupont E, et al. Identification of a neural-specific cDNA, NPDC-1, able to down-regulate cell proliferation and to suppress transformation. Proc Natl Acad Sci U S A 1995; 92: 1560–4.
Dupont E, Sansal I, Evrard C, Rouget P. Developmental pattern of expression of NPDC-1 and its interaction with E2F-1 suggest a role in the control of proliferation and differentiation of neural cells. J Neurosci Res 1998; 51: 257–67.
Zhang K, Kniazeva M, Han M, et al. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 2001; 27: 89–93.
Donoso LA, Edwards AO, Frost A, et al. Autosomal dominant Stargardt-like macular dystrophy. Surv Ophthalmol 2001; 46: 149–63.
Shah GV, Rayford W, Noble MJ, et al. Calcitonin stimulates growth of human prostate cancer cells through receptor-mediated increase in cyclic adenosine 3′,5′-monophosphates and cytoplasmic Ca2+ transients. Endocrinology 1994; 134: 596–602.
Chien J, Ren Y, Qing Wang Y, et al. Calcitonin is a prostate epithelium-derived growth stimulatory peptide. Mol Cell Endocrinol 2001; 181: 69–79.
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Bloomston, M., Durkin, A., Yang, I. et al. Identification of Molecular Markers Specific for Pancreatic Neuroendocrine Tumors by Genetic Profiling of Core Biopsies. Ann Surg Oncol 11, 413–419 (2004). https://doi.org/10.1245/ASO.2004.03.077
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DOI: https://doi.org/10.1245/ASO.2004.03.077