Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer and Metastasis Reviews
Published in: Cancer and Metastasis Reviews 1-2/2012

01-06-2012 | NON-THEMATIC REVIEW

Gastroenteropancreatic neuroendocrine tumor cancer stem cells: do they exist?

Authors: Enrique Grande, Jaume Capdevila, Jorge Barriuso, Luis Antón-Aparicio, Daniel Castellano

Published in: Cancer and Metastasis Reviews | Issue 1-2/2012

Login to get access

Abstract

Neuroendocrine tumors (NETs) comprise a broad range of neoplasms that share biological and embryological origin. A deeper knowledge in the underlying molecular biology that results in the development and spread of NETs has allowed the use of novel-targeted therapies against angiogenesis and intracellular pathways, key checkpoints that govern growth, and proliferation of these tumors. Unfortunately, the possibility of cure is still far for patients with advanced stages. Cancer stem cells (CSCs) are present in most solid tumors. Nevertheless, there is limited evidence for the presence of CSCs in NETs. In this review, we will discuss the embryonic origin and possible existence of a gastroenteropancreatic neuroendocrine cancer stem cell. Here, we summarize the body of evidence supporting the presence of active embryological pathways like Notch, Wnt-β-catenin, Hedgehog, or transforming growth factor-β in NETs. New therapeutic approaches in the field of CSCs seem to have a clear role in the treatment of medulloblastomas and basal cell carcinomas, but their future value in other solid tumor types including NETs remains unclear.
Literature
1.
Andrew, A., Kramer, B., & Rawdon, B. B. (1998). The origin of gut and pancreatic neuroendocrine (APUD) cells—the last word? The Journal of Pathology, 186(2), 117–118.PubMedCrossRef
2.
Modlin, I. M., Oberg, K., Chung, D. C., Jensen, R. T., de Herder, W. W., et al. (2008). Gastroenteropancreatic neuroendocrine tumours. The Lancet Oncology, 9(1), 61–72.PubMedCrossRef
3.
Hauso, O., Gustafsson, B. I., Kidd, M., Waldum, H. L., Drozdov, I., et al. (2008). Neuroendocrine tumor epidemiology: Contrasting Norway and North America. Cancer, 113(10), 2655–2664.PubMedCrossRef
4.
ESMO Guidelines Working Group, Oberg, K., Akerström, G., Rindi, G., & Jelic, S. (2010). Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 21(Suppl 5), v223–v227.PubMedCrossRef
5.
Oberg, K., Hellman, P., Kwekkeboom, D., Jelic, S; ESMO Guidelines Working Group. (2010). Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 21(Suppl 5), v220–v222.PubMedCrossRef
6.
Raymond, E., Niccoli, P., Raoul, J., Bang, Y., Borbath, I., et al. (2010). Cox proportional hazard analysis of sunitinib (SU) efficacy across subgroups of patients (pts) with progressive pancreatic neuroendocrine tumors (NET). Journal of Clinical Oncology, 28, 7s (suppl; abstr 4031).CrossRef
7.
Pavel, M., Hainsworth, J., Baudin, E., Peeters, M., Hoersch, D., Anthony, L., et al. (2010). Randomized, phase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR in patients with advanced neuroendocrine tumours (NET) (RADIANT-2). Annals of Oncology, 21(Suppl 8), LBA8.
8.
Yao, J., Shah, M., Ito, T., Lombard-Bohas, C., Wolin, E., et al. (2010). Phase III randomized trial of everolimus (RAD001) vs placebo in advanced pancreatic NET (RADIANT-3). Annals of Oncology, 21(Suppl 8), LBA9.
9.
Hobday, T. J., Rubin, J., Holen, K., Picus, J., Donehower, R., et al. (2007). MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A phase II consortium (P2C) study. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement):4504.
10.
Phan, A. T., Yao, J. C., Fogelman, D. R., Hess, K. R., Ng, C. S., et al. (2010). Pazopanib and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). Journal of Clinical Oncology, 28, 7. s(suppl; abstr 4001).CrossRef
11.
Yao, J. C., Phan, A., Hoff, P. M., Chen, H. X., Charnsangavej, C., et al. (2008). Targeting vascular endothelial growth factor in advanced carcinoid tumor: A random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. Journal of Clinical Oncology, 26(8), 1316–1323.PubMedCrossRef
12.
Duran, I., Kortmansky, J., Singh, D., Hirte, H., Kocha, W., et al. (2006). A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. British Journal of Cancer, 95(9), 1148–1154.PubMedCrossRef
13.
Lam, E. T., Ringel, M. D., Kloos, R. T., Prior, T. W., Knopp, M. V., et al. (2010). Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. Journal of Clinical Oncology, 28(14), 2323–2330.PubMedCrossRef
14.
Bible, K. C., Suman, V. J., Molina, J. R., Smallridge, R. C., Maples, W. J., et al. (2010). Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study. The Lancet Oncology, 11(10), 962–972.PubMedCrossRef
15.
Carr, L. L., Mankoff, D. A., Goulart, B. H., Eaton, K. D., Capell, P. T., et al. (2010). Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clinical Cancer Research, 16(21), 5260–5268.PubMedCrossRef
16.
Houghton, J., Morozov, A., Smirnova, I., & Wang, T. C. (2007). Stem cells and cancer. Seminars in Cancer Biology, 17(3), 191–203.PubMedCrossRef
17.
Cobaleda, C., Gutiérrez-Cianca, N., Pérez-Losada, J., Flores, T., García-Sanz, R., et al. (2000). A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood, 95(3), 1007–1013.PubMed
18.
Dontu, G., Al-Hajj, M., Abdallah, W. M., Clarke, M. F., & Wicha, M. S. (2003). Stem cells in normal breast development and breast cancer. Cell Proliferation, 36(Suppl 1), 59–72.PubMedCrossRef
19.
Hemmati, H. D., Nakano, I., Lazareff, J. A., Masterman-Smith, M., Geschwind, D. H., et al. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences of the United States of America, 100(25), 15178–15183.PubMedCrossRef
20.
O’Brien, C. A., Pollett, A., Gallinger, S., & Dick, J. E. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 445(7123), 106–110.PubMedCrossRef
21.
Fang, D., Nguyen, T. K., Leishear, K., Finko, R., Kulp, A. N., et al. (2005). A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Research, 65(20), 9328–9337.PubMedCrossRef
22.
Hermann, P. C., Huber, S. L., Herrler, T., Aicher, A., Ellwart, J. W., et al. (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 1(3), 313–323.PubMedCrossRef
23.
Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J., & Maitland, N. J. (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Research, 65(23), 10946–10951.PubMedCrossRef
24.
Bapat, S. A., Mali, A. M., Koppikar, C. B., & Kurrey, N. K. (2005). Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Research, 65(8), 3025–3029.PubMed
25.
Ma, S., Chan, K. W., Hu, L., Lee, T. K., Wo, J. Y., et al. (2007). Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology, 132(7), 2542–2556.PubMedCrossRef
26.
Ho, M. M., Ng, A. V., Lam, S., & Hung, J. Y. (2007). Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Research, 67(10), 4827–4833.PubMedCrossRef
27.
Fukuda, K., Saikawa, Y., Ohashi, M., Kumagai, K., Kitajima, M., et al. (2009). Tumor initiating potential of side population cells in human gastric cancer. International Journal of Oncology, 34(5), 1201–1207.PubMed
28.
Todaro, M., Iovino, F., Eterno, V., Cammareri, P., Gambara, G., Espina, V., et al. (2010). Tumorigenic and metastatic activity of human thyroid cancer stem cells. Cancer Research, 70(21), 8874–8885.PubMedCrossRef
29.
Bomken, S., Fiser, K., Heidenreich, O., & Vormoor, J. (2010). Understanding the cancer stem cell. British Journal of Cancer, 103(4), 439–445.PubMedCrossRef
30.
Andrew, A., Kramer, B., & Rawdon, B. B. (1982). The embryonic origin of endocrine cells of the gastrointestinal tract. General and Comparative Endocrinology, 47(2), 249–265.PubMedCrossRef
31.
Waldum, H. L., Sandvik, A. K., Angelsen, A., Krokan, H., & Falkmer, S. (1999). Re: Editorial entitled ‘The origin of gut and pancreatic neuroendocrine (APUD) cells–the last word?’. The Journal of Pathology, 188(1), 113–114.PubMedCrossRef
32.
Kramer, B., & Andrew, A. (1981). Further investigation into the source of pancreatic endocrine cell types. General and Comparative Endocrinology, 44, 279–287.PubMedCrossRef
33.
Andrew, A. (1981). APUD cells and paraneurons: Embryonic origin. In S. FederoV & L. Hertz (Eds.), Advances in cellular neurobiology (Vol. 2, pp. 3–32). New York: Academic Press.
34.
Dieterlen-Lièvre, F., & Beaupain, D. (1976). Immunocytological study of endocrine pancreas ontogeny in the chick embryo: Normal development and pancreatic potentialities in the early splanchnopleure. In T. A. I. Grillo, L. Liebson, & A. Epple (Eds.), The Evolution of Pancreatic Islets (pp. 37–50). Oxford: Pergamon Press.
35.
Fontaine, J., Le Lièvre, C., & Le Douarin, N. M. (1977). What is the developmental fate of the neural crest cells which migrate into the pancreas in the avian embryo? General and Comparative Endocrinology, 33, 394–404.PubMedCrossRef
36.
Andrew, A., & Kramer, B. (1979). An experimental investigation into the possible origin of pancreatic islet cells from rhombencephalic neurectoderm. Journal of Embryology and Experimental Morphology, 52, 23–33.PubMed
37.
Fontaine-Pèrus, J., Le Lièvre, C., & Dubois, M. P. (1980). Do neural crest cells in the pancreas differentiate into somatostatin-containing cells? Cell and Tissue Research, 213, 293–299.PubMedCrossRef
38.
Le Douarin, N., & Teillet, M.-A. (1973). The migration of neural crest cells to the wall of the digestive tract in avian embryo. Journal of Embryology and Experimental Morphology, 30, 31–48.PubMed
39.
Fontaine, J., & Le Douarin, N. M. (1977). Analysis of endoderm formation in the avianblastoderm by the use of quail-chick chimaeras. The problem of the neuroectodermal origin of the cells of the APUD series. Journal of Embryology and Experimental Morphology, 41, 209–222.PubMed
40.
Gestblom, C., Hoehner, J. C., Hedborg, F., et al. (1997). In vivo spontaneous neuronal to neuroendocrine lineage conversion in a subset of neuroblastomas. American Journal of Pathology, 150, 107–117.PubMed
41.
van Eeden, S., & Offerhaus, G. J. (2006). Historical, current and future perspectives on gastrointestinal and pancreatic endocrine tumors. Virchows Archiv, 448(1), 1–6.PubMedCrossRef
42.
Schonhoff, S. E., Giel-Moloney, M., & Leiter, A. B. (2004). Minireview: Development and differentiation of gut endocrine cells. Endocrinology, 145(6), 2639–2644.PubMedCrossRef
43.
Schwitzgebel, V. M. (2001). Programming of the pancreas. Molecular and Cellular Endocrinology, 185(1–2), 99–108.PubMedCrossRef
44.
Dumortier, J., Ratineau, C., Scoazec, J. Y., Pourreyron, C., Anderson, W., et al. (2000). Site-specific epithelial-mesenchymal interactions in digestive neuroendocrine tumors. An experimental in vivo and in vitro study. American Journal of Pathology, 156(2), 671–683.PubMedCrossRef
45.
Pannuti, A., Foreman, K., Rizzo, P., Osipo, C., Golde, T., et al. (2010). Targeting Notch to target cancer stem cells. Clinical Cancer Research, 16(12), 3141–3152.PubMedCrossRef
46.
Darville, M. I., & Eizirik, D. L. (2006). Notch signaling: A mediator of beta-cell de-differentiation in diabetes? Biochemical and Biophysical Research Communications, 339(4), 1063–1068.PubMedCrossRef
47.
Kunnimalaiyaan, M., & Chen, H. (2007). Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. The Oncologist, 12(5), 535–542.PubMedCrossRef
48.
Nakakura, E. K., Sriuranpong, V. R., Kunnimalaiyaan, M., Hsiao, E. C., Schuebel, K. E., et al. (2005). Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling. Journal of Clinical Endocrinology and Metabolism, 90(7), 4350–4356.PubMedCrossRef
49.
Merchant, A. A., & Matsui, W. (2010). Targeting Hedgehog—a cancer stem cell pathway. Clinical Cancer Research, 16(12), 3130–3140.PubMedCrossRef
50.
Fendrich, V., Waldmann, J., Esni, F., Ramaswamy, A., Mullendore, M., et al. (2007). Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum. Endocrine-Related Cancer, 14(3), 865–874.PubMedCrossRef
51.
Shida, T., Furuya, M., Nikaido, T., Hasegawa, M., Koda, K., et al. (2006). Sonic Hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine carcinomas. Cancer Biology & Therapy, 5(11), 1530–1538.CrossRef
52.
Takebe, N., & Ivy, S. P. (2010). Controversies in cancer stem cells: Targeting embryonic signaling pathways. Clinical Cancer Research, 16(12), 3106–3112.PubMedCrossRef
53.
Takahashi-Yanaga, F., & Kahn, M. (2010). Targeting Wnt signaling: Can we safely eradicate cancer stem cells? Clinical Cancer Research, 16(12), 3153–3162.PubMedCrossRef
54.
Su, M. C., Wang, C. C., Chen, C. C., Hu, R. H., Wang, T. H., et al. (2006). Nuclear translocation of beta-catenin protein but absence of beta-catenin and APC mutation in gastrointestinal carcinoid tumor. Annals of Surgical Oncology, 13(12), 1604–1609.PubMedCrossRef
55.
Chen, G., A, J., Wang, M., Farley, S., Lee, L. Y., Lee, L. C., et al. (2008). Menin promotes the Wnt signaling pathway in pancreatic endocrine cells. Molecular Cancer Research, 6(12), 1894–1907.PubMed
56.
Iwatsuki, M., Mimori, K., Yokobori, T., Ishi, H., Beppu, T., et al. (2010). Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Science, 101(2), 293–299.PubMedCrossRef
57.
Bierie, B., & Moses, H. L. (2006). Tumour microenvironment: TGFbeta: The molecular Jekyll and Hyde of cancer. Nature Reviews. Cancer, 6(7), 506–520.PubMedCrossRef
58.
Zhang, P. J., Furth, E. E., Cai, X., Goldblum, J. R., Pasha, T. L., & Min, K. W. (2004). The role of beta-catenin, TGF beta 3, NGF2, FGF2, IGFR2, and BMP4 in the pathogenesis of mesenteric sclerosis and angiopathy in midgut carcinoids. Human Pathology, 35(6), 670–674.PubMedCrossRef
59.
Zuetenhorst, J. M., Bonfrer, J. M., Korse, C. M., Bakker, R., van Tinteren, H., & Taal, B. G. (2003). Carcinoid heart disease: The role of urinary 5-hydroxyindoleacetic acid excretion and plasma levels of atrial natriuretic peptide, transforming growth factor-beta and fibroblast growth factor. Cancer, 97(7), 1609–1615.PubMedCrossRef
60.
Bergers, G., & Hanahan, D. (2008). Modes of resistance to anti-angiogenic therapy. Nature Reviews. Cancer, 8(8), 592–603.PubMedCrossRef
61.
Visvader, J. E., & Lindeman, G. J. (2008). Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nature Reviews. Cancer, 8(10), 755–768.PubMedCrossRef
62.
Takebe, N., Harris, P. J., Warren, R. Q., & Ivy, S. P. (2011). Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nature Reviews Clinical Oncology, 8, 97–106.PubMedCrossRef
63.
Metadata
Title
Gastroenteropancreatic neuroendocrine tumor cancer stem cells: do they exist?
Authors
Enrique Grande
Jaume Capdevila
Jorge Barriuso
Luis Antón-Aparicio
Daniel Castellano
Publication date
01-06-2012
Publisher
Springer US
Published in
Cancer and Metastasis Reviews / Issue 1-2/2012
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI
https://doi.org/10.1007/s10555-011-9328-6

Other articles of this Issue 1-2/2012

Cancer and Metastasis Reviews 1-2/2012 Go to the issue

NON-THEMATIC REVIEW

Flavonoids, a ubiquitous dietary phenolic subclass, exert extensive in vitro anti-invasive and in vivo anti-metastatic activities

NON-THEMATIC REVIEW

The present and future of gene profiling in breast cancer

NON-THEMATIC REVIEW

Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression

NON-THEMATIC REVIEW

The Eph/Ephrin family in cancer metastasis: communication at the service of invasion

NON-THEMATIC REVIEW

In vivo animal models of spinal metastasis

NON-THEMATIC REVIEW

The genetic/metabolic transformation concept of carcinogenesis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits