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Biological Behavior of Malignant Melanoma Cells Correlated to Their Survival in Vivo¹

Department of Pathology, Schools of Dental Medicine and Medicine and Center for Oral Health Research, University of Pennsylvania, Philadelphia, Pennsylvania 19174

Successive B16 melanoma tumor lines were selected for their ability to form pulmonary tumor nodules. This was accomplished by injecting tumor cells i.v. into syngeneic C57BL/6 mice and 2 to 3 weeks later collecting the secondary tumor growths and placing them into tissue culture. These tumor cells were then injected i.v. into new syngeneic mice and the process was repeated several times. With each successive tumor line the number of experimental lung tumor nodules was significantly increased. The B16 lines were found to be stable in their metastatic properties even after many subculturings in vitro.

These studies demonstrated that tumor cells that succeed in forming pulmonary tumor colonies also had increased invasive properties into normal tissues when implanted s.c. In addition, the tumor cell lines were prelabeled in vitro with [¹²⁵I]-5-iodo-2'-deoxyuridine and suspensions of labeled cells were injected i.v. into normal syngeneic hosts. Animals were killed at intervals afterwards, and the lungs and blood were processed and monitored for radioactivity. At any time interval, the lungs of mice treated by injections of cells of high metastatic yield contained more tumor cells. The differences in tumor cell numbers in the lungs were most pronounced immediately following i.v. injection. These results suggest that an increased initial arrest of highly metastatic cells in a capillary bed may be a major factor in their increased survival.

Low numbers of normal lymphocytes or lymphocytes from syngeneic mice immunized to the B16 melanoma, when mixed in vitro with the tumor cells, lead to the formation of multitumor cell-lymphocyte clumps. The degree of clumping was related to both the type of the metastatic tumor line and/or the syngeneic lymphocyte.

These results support the hypothesis that the survival of invasive and/or circulating malignant tumor cells is not a random phenomenon; rather it appears that malignant cells possess unique qualities which allow for their survival.

¹ Supported by USPHS Grants CA 12456 and DE 02623.

Received 6/ 4/74. Accepted 10/ 3/74.

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				R. M. Sullivan, M. Stone, J. F. Marshall, F. Uberall, and S. A. Rotenberg Photo-Induced Inactivation of Protein Kinase Calpha by Dequalinium Inhibits Motility of Murine Melanoma Cells Mol. Pharmacol., October 1, 2000; 58(4): 729 - 737. [Abstract] [Full Text]

				M. D. Cameron, E. E. Schmidt, N. Kerkvliet, K. V. Nadkarni, V. L. Morris, A. C. Groom, A. F. Chambers, and I. C. MacDonald Temporal Progression of Metastasis in Lung: Cell Survival, Dormancy, and Location Dependence of Metastatic Inefficiency Cancer Res., May 1, 2000; 60(9): 2541 - 2546. [Abstract] [Full Text]

				Z.-K. Pan, L. M. Weiskirch, and Y. Paterson Regression of Established B16F10 Melanoma with a Recombinant Listeria monocytogenes Vaccine Cancer Res., October 1, 1999; 59(20): 5264 - 5269. [Abstract] [Full Text] [PDF]

				A.-M. Khatib, M. Kontogiannea, L. Fallavollita, B. Jamison, S. Meterissian, and P. Brodt Rapid Induction of Cytokine and E-Selectin Expression in the Liver in Response to Metastatic Tumor Cells Cancer Res., March 1, 1999; 59(6): 1356 - 1361. [Abstract] [Full Text] [PDF]

				M. Hejna, M. Raderer, and C. C. Zielinski Inhibition of Metastases by Anticoagulants J Natl Cancer Inst, January 6, 1999; 91(1): 22 - 36. [Abstract] [Full Text] [PDF]

				K. Hung, R. Hayashi, A. Lafond-Walker, C. Lowenstein, D. Pardoll, and H. Levitsky The Central Role of CD4+ T Cells in the Antitumor Immune Response J. Exp. Med., December 21, 1998; 188(12): 2357 - 2368. [Abstract] [Full Text] [PDF]

				O. V. Volpert, J. Lawler, and N. P. Bouck A human fibrosarcoma inhibits systemic angiogenesis and the growth of experimental metastases via thrombospondin-1 PNAS, May 26, 1998; 95(11): 6343 - 6348. [Abstract] [Full Text] [PDF]

				M Hofmann, C Fieber, V Assmann, M Gottlicher, J Sleeman, R Plug, N Howells, O von Stein, H Ponta, and P Herrlich Identification of IHABP, a 95 kDa intracellular hyaluronate binding protein J. Cell Sci., January 6, 1998; 111(12): 1673 - 1684. [Abstract] [PDF]

				D. M. Ashley, B. Faiola, S. Nair, L. P. Hale, D. D. Bigner, and E. Gilboa Bone Marrow-generated Dendritic Cells Pulsed with Tumor Extracts or Tumor RNA Induce Antitumor Immunity against Central Nervous System Tumors J. Exp. Med., October 6, 1997; 186(7): 1177 - 1182. [Abstract] [Full Text] [PDF]

				J. Niederkorn, G. E. Sanborn, and E. E. Scarbrough Mouse Model of Brachytherapy in Consort With Enucleation for Treatment of Malignant Intraocular Melanoma Arch Ophthalmol, June 1, 1990; 108(6): 865 - 868. [Abstract] [PDF]

				G. Rice and M. Bevilacqua An inducible endothelial cell surface glycoprotein mediates melanoma adhesion Science, December 8, 1989; 246(4935): 1303 - 1306. [Abstract] [PDF]

				G. E. Sanborn, P. Ngyuen, J. Gamel, and J. Y. Niederkorn Reduction of Enucleation-Induced Metastasis in Intraocular Melanoma by Periorbital Irradiation Arch Ophthalmol, September 1, 1987; 105(9): 1260 - 1264. [Abstract] [PDF]

				R. Hill, A. Chambers, V Ling, and J. Harris Dynamic heterogeneity: rapid generation of metastatic variants in mouse B16 melanoma cells Science, June 1, 1984; 224(4652): 998 - 1001. [Abstract] [PDF]

				I. Fidler and I. Hart Biological diversity in metastatic neoplasms: origins and implications Science, September 10, 1982; 217(4564): 998 - 1003. [Abstract] [PDF]

				G. Nicolson and S. Custead Tumor metastasis is not due to adaptation of cells to a new organ environment Science, January 8, 1982; 215(4529): 176 - 178. [Abstract] [PDF]

				I. Fidler and M. Kripke Metastasis results from preexisting variant cells within a malignant tumor Science, August 26, 1977; 197(4306): 893 - 895. [Abstract] [PDF]

				T. S. Kuroda, M. Fukuda, H. Ariga, and K. Mikoshiba The Slp Homology Domain of Synaptotagmin-like Proteins 1-4 and Slac2 Functions as a Novel Rab27A Binding Domain J. Biol. Chem., March 8, 2002; 277(11): 9212 - 9218. [Abstract] [Full Text] [PDF]

				J. H. Sampson, L. E. Crotty, S. Lee, G. E. Archer, D. M. Ashley, C. J. Wikstrand, L. P. Hale, C. Small, G. Dranoff, A. H. Friedman, et al. Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors PNAS, June 20, 2000; 97(13): 7503 - 7508. [Abstract] [Full Text] [PDF]