A transplantable human carcinoid as model for somatostatin receptor-mediated and amine transporter-mediated radionuclide uptake.
A human midgut carcinoid tumor was successfully transplanted into nude mice and propagated for five consecutive generations (30 months) with well-preserved phenotype. Tumor cells in nude mice expressed identical neuroendocrine markers as the original tumor, including somatostatin receptors (somatostatin receptors 1 to 5) and vesicular monoamine transporters (VMAT1 and VMAT2). Because of the expression of somatostatin receptors and VMAT1 and VMAT2 the grafted tumors could be visualized scintigraphically using the somatostatin analogue 111In-octreotide and the catecholamine analogue 123I-metaiodobenzylguanidine. The biokinetics of the somatostatin analogue 111In-octreotide in the tumors was studied and showed a high retention 7 days after administration. Cell cultures were re-established from transplanted tumors. Immunocytochemical and ultrastructural studies confirmed the neuroendocrine differentiation. The human origin of transplanted tumor cells was confirmed by cytogenetic and fluorescence it situ hybridization analyses. Spontaneous secretion of serotonin and its metabolite, 5-hydroxyindole acetic acid, from tumor cells was demonstrated. The tumor cells increased their [Ca2+]i in response to beta-adrenoceptor stimulation (isoproterenol) and K+-depolarization. All somatostatin receptor subtypes could be demonstrated in cultured cells. This human transplantable carcinoid tumor, designated GOT1, grafted to nude mice, will give unique possibilities for studies of somatostatin receptor- and VMAT-mediated radionuclide uptake as well as for studies of secretory mechanisms.
Kölby
L
L
Lundberg Laboratory for Cancer Research, the Department of Surgery, Sahlgrenska University Hospital, University of Göteberg, Göteberg, Sweden. lars.kolby@surgery.gu.se
Bernhardt
P
P
Ahlman
H
H
Wängberg
B
B
Johanson
V
V
Wigander
A
A
Forssell-Aronsson
E
E
Karlsson
S
S
Ahrén
B
B
Stenman
G
G
Nilsson
O
O
D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics; D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002276:Carcinoid Tumor / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D053379:Chromogranin A; D002864:Chromogranins / Q000032:analysis; D020223:Chromosome Painting; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007078:Ileal Neoplasms / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D026901:Membrane Transport Proteins; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009479:Neuropeptides; D015282:Octreotide / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011868:Radioisotopes / Q000493:pharmacokinetics; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D013373:Substance P / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D001679:Biogenic Amines; D002352:Carrier Proteins; D053379:Chromogranin A; D002864:Chromogranins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D011868:Radioisotopes; D017481:Receptors, Somatostatin; C493449:SLC18A1 protein, human; C493452:SLC18A2 protein, human; C493450:Slc18a1 protein, mouse; C493453:Slc18a2 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin; D013373:Substance P; D019797:3-Iodobenzylguanidine; D006897:Hydroxyindoleacetic Acid; D006916:5-Hydroxytryptophan; D015282:Octreotide; D002118:Calcium