Hostname: page-component-8448b6f56d-tj2md Total loading time: 0 Render date: 2024-04-24T20:36:27.581Z Has data issue: false hasContentIssue false
  • English
  • Français

Gastro-Enteropancreatic Neuroendocrine Tumor Cell Dynamics in Liver Microvasculature

Published online by Cambridge University Press:  29 April 2015

Priyodarshan Goswamee ,
Sasi Arunachalam ,
Saurabh Mehta ,
Riaz Nasim ,
William T. Gunning III  and
David R. Giovannucci
Priyodarshan Goswamee
Affiliation:
Department of Neurosciences, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA
Sasi Arunachalam
Affiliation:
Department of Neurosciences, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA
Saurabh Mehta
Affiliation:
Department of Neurosciences, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA
Riaz Nasim
Affiliation:
Department of Pharmacology, Peshawar Medical College, Warsak Road Peshawar, Khyber Pakhtunkhwa 25160, Pakistan
William T. Gunning III
Affiliation:
Department of Pathology, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA
David R. Giovannucci*
Affiliation:
Department of Neurosciences, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA
*
*Corresponding author.david.giovannucci@utoledo.edu
Get access

Abstract

For many cancers, liver metastasis is common and usually indicates poor prognosis. Gastro-enteropancreatic neuroendocrine tumors (GEPNETs) of the midgut are a heterogeneous group of cancers that typically remain asymptomatic until they metastasize to the liver. However, the mechanisms by which these usually indolent cancers establish distal metastasis remain unclear.

To begin to elucidate this process, we performed standard in vitro assays to assess cell motility, transendothelial migration, and invasion using BON cells, a widely used model GEPNET cell line. In addition, transmission electron microscopy was used in combination with a novel ex vivo organ slice xenograft model to reveal ultrastructural details of the initial events of BON cell extravasation and re-distribution within the liver. The ultrastructural resolution of the extravasation process revealed the route, sequence, and time course by which tumor cells migrated from the sinusoidal lumen into the hepatic parenchyma in this organ slice model. Both standard in vitro assays and our organ slice model indicated that tumor cells migrated through the discontinuous sinusoidal endothelium to invade the liver parenchyma.

Keywords

extravasationliver metastasisGEPNETorganotypic sliceultrastructure
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 21 , Issue 3 , June 2015 , pp. 655 - 665
Copyright
© Microscopy Society of America 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Berge, T. & Linell, F. (1976). Carcinoid tumours. Frequency in a defined population during a 12-year period. Acta Pathol Microbiol Scand A 84(4), 322–330.Google Scholar
Bhattacharyya, S., Gujral, D.M., Toumpanakis, C., Dreyfus, G., Davidson, B.R., Davar, J. & Caplin, M.E. (2009). A stepwise approach to the management of metastatic midgut carcinoid tumor. Nat Rev Clin Oncol 6(7), 429–433.CrossRefGoogle Scholar
Chambers, A.F., Groom, A.C. & MacDonald, I.C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8), 563–572.Google Scholar
de Vries, H., Verschueren, R.C., Willemse, P.H., Kema, I.P. & de Vries, E.G. (2002). Diagnostic, surgical and medical aspect of the midgut carcinoids. Cancer Treat Rev 28(1), 11–25.Google Scholar
Debbaut, C., Segers, P., Cornillie, P., Casteleyn, C., Dierick, M., Laleman, W. & Monbaliu, D. (2014). Analyzing the human liver vascular architecture by combining vascular corrosion casting and micro-CT scanning: A feasibility study. J Anat 224(4), 509–517.CrossRefGoogle ScholarPubMed
Di Florio, A., Sancho, V., Moreno, P., Delle Fave, G. & Jensen, R.T. (2013). Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor. Biochim Biophys Acta 1833(3), 573–582.Google Scholar
Evers, B.M., Hurlbut, S.C., Tyring, S.K., Townsend, C.M. Jr., Uchida, T. & Thompson, J.C. (1991 a). Novel therapy for the treatment of human carcinoid. Ann Surg 213(5), 411–416.CrossRefGoogle ScholarPubMed
Evers, B.M., Townsend, C.M. Jr., Upp, J.R., Allen, E., Hurlbut, S.C., Kim, S.W., Rajaraman, S., Singh, P., Reubi, J.C. & Thompson, J.C. (1991 b). Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth. Gastroenterology 101(2), 303–311.Google Scholar
Evers, B.M., Ishizuka, J., Townsend, C.M. Jr. & Thompson, J.C. (1994). The human carcinoid cell line, BON. A model system for the study of carcinoid tumors. Ann N Y Acad Sci 733, 393–406.Google Scholar
Fazio, N., Di Meglio, G., Lorizzo, K. & de Brand, F. (2008). Miliary hepatic metastases from neuroendocrine carcinoma. Dig Surg 25(5), 330.Google Scholar
Fidler, I.J. (2003). The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3(6), 453–458.Google Scholar
Gassmann, P., Hemping-Bovenkerk, A., Mees, S.T. & Haier, J. (2009). Metastatic tumor cell arrest in the liver-lumen occlusion and specific adhesion are not exclusive. Int J Colorectal Dis 24(7), 851–858.Google Scholar
Gu, P., Wu, J., Newman, E. & Muggia, F. (2012). Treatment of liver metastases in patients with neuroendocrine tumors of gastroesophageal and pancreatic origin. Int J Hepatol 2012, 131659, 1–8.CrossRefGoogle ScholarPubMed
Huebert, R.C., Jagavelu, K., Liebl, A.F., Huang, B.Q., Splinter, P.L., LaRusso, N.F., Urrutia, R.A. & Shah, V.H. (2010). Immortalized liver endothelial cells: A cell culture model for studies of motility and angiogenesis. Lab Invest 90(12), 1770–1781.Google Scholar
Ishizuka, J., Beauchamp, R.D., Townsend, C.M. Jr., Greeley, G.H. Jr. & Thompson, J.C. (1992). Receptor-mediated autocrine growth-stimulatory effect of 5-hydroxytryptamine on cultured human pancreatic carcinoid cells. J Cell Physiol 150(1), 1–7.CrossRefGoogle ScholarPubMed
Jackson, L.N., Chen, L.A., Larson, S.D., Silva, S.R., Rychahou, P.G., Boor, P.J., Li, J., Defreitas, G., Stafford, W.L., Townsend, C.M. Jr. & Evers, B.M. (2009). Development and characterization of a novel in vivo model of carcinoid syndrome. Clin Cancer Res 15(8), 2747–2755.Google Scholar
Jiménez-Castro, M.B., Elias-Miró, M., Casillas-Ramírez, A., & Peralta, C. (2013). Experimental Models in Liver Surgery. In Hepatic Surgery, Abdeldayem, H. (Ed.), pp. 121–166. Rijeka, Croatia: InTech. ISBN: 978-953-51-0965-5.Google Scholar
John, B.J. & Davidson, B.R. (2012). Treatment options for unresectable neuroendocrine liver metastases. Expert Rev Gastroenterol Hepatol 6(3), 357–369.Google Scholar
Modlin, I.M., Lye, K.D. & Kidd, M. (2003). A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97(4), 934–959.Google Scholar
Modlin, I.M. & Sandor, A. (1997). An analysis of 8305 cases of carcinoid tumors. Cancer 79(4), 813–829.Google Scholar
Musunuru, S., Carpenter, J.E., Sippel, R.S., Kunnimalaiyaan, M. & Chen, H. (2005). A mouse model of carcinoid syndrome and heart disease. J Surg Res 126(1), 102–105.CrossRefGoogle ScholarPubMed
Oberg, K., Astrup, L., Eriksson, B., Falkmer, S.E., Falkmer, U.G., Gustafsen, J., Haglund, C., Knigge, U., Vatn, M.H., Valimaki, M. & Nordic, N.E.T.G. (2004). Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I-general overview. Acta Oncol 43(7), 617–625.Google Scholar
Rahner, C., Mitic, L.L. & Anderson, J.M. (2001). Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut. Gastroenterology 120(2), 411–422.Google Scholar
Robertson, R.G., Geiger, W.J. & Davis, N.B. (2006). Carcinoid tumors. Am Fam Physician 74(3), 429–434.Google Scholar
Saha, S., Hoda, S., Godfrey, R., Sutherland, C. & Raybon, K. (1989). Carcinoid tumors of the gastrointestinal tract: A 44-year experience. South Med J 82(12), 1501–1505.Google Scholar
van der Lely, A.J. & de Herder, W.W. (2005). Carcinoid syndrome: Diagnosis and medical management. Arq Bras Endocrinol Metabol 49(5), 850–860.Google Scholar
Vikman, S., Essand, M., Cunningham, J.L., de la Torre, M., Oberg, K., Totterman, T.H. & Giandomenico, V. (2005). Gene expression in midgut carcinoid tumors: Potential targets for immunotherapy. Acta Oncol 44(1), 32–40.Google Scholar
von Wichert, G., Jehle, P.M., Hoeflich, A., Koschnick, S., Dralle, H., Wolf, E., Wiedenmann, B., Boehm, B.O., Adler, G. & Seufferlein, T. (2000). Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res 60(16), 4573–4581.Google Scholar
Yao, J.C., Hassan, M., Phan, A., Dagohoy, C., Leary, C., Mares, J.E., Abdalla, E.K., Fleming, J.B., Vauthey, J.N., Rashid, A. & Evans, D.B. (2008). One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26(18), 3063–3072.Google Scholar
Supplementary material: Image

Goswamee supplementary material S1

Figure

Download Goswamee supplementary material S1(Image)
Image 18.6 MB

Goswamee supplementary material S2

Supplementary movie

Download Goswamee supplementary material S2(Video)
Video 4.2 MB