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Heterotopic implantation alters the regulation of apoptosis and the cell cycle and generates a new metastatic site in a human pancreatic tumor xenograft model

LOURDES FARRÉ, ISOLDA CASANOVA, SÍLVIA GUERRERO, MANUEL TRIAS^*, GABRIEL CAPELLÀ and RAMON MANGUES¹

Institut de Recerca and
^* Department of Surgery of the Hospital de la Santa Creu i Sant Pau, Barcelona; and
Laboratori de Recerca Translacional of the Institut Català d’Oncologia, Barcelona, Spain

¹Correspondence: Institut de Recerca, Hospital de Sant Pau, Avda. Sant Antoni M. Claret, 167, Barcelona, Spain. E-mail: rmangues{at}santpau.es

Differences in growth and in response to antineoplastic drugs between s.c. and orthotopically implanted tumors in nude mice and between the primary tumor and the metastases in human tumors suggest that implantation site may alter the molecular regulation of tumor cells. We assessed the influence of implantation site on cell cycle and apoptotic regulation and the possible contribution of the implantation site in directing the choice of metastatic site by comparing the behavior of tumor aliquots of two human pancreatic xenografts (NP18 and NP9) implanted in the organ where the tumor grows (orthotopically), in heterotopic sites (the site of metastases (liver), and in nonmetastatic sites (subcutis and colon). We observed that implantation site changes tumor growth by altering apoptotic or cell cycle regulation in a tumor-specific manner. In the NP18 tumor it occurs by altering apoptotic induction and activation of the Bad/Bcl-X_L/caspase-3 pathway through AKT and Erk regulation, but in the NP9 tumor by changing the activation and/or expression of the proteins that regulate the cell cycle (Erk, PCNA, and cyclin B1). We also observed that implantation site alters the metastatic pattern of the NP9 tumor, originating a new metastatic site.—Farré, L., Casanova, I., Guerrero, S., Trias, M., Capellà, G., Mangues, R. Heterotopic implantation alters the regulation of apoptosis and the cell cycle and generates a new metastatic site in a human pancreatic tumor xenograft model.

Key Words: implantation site • carcinoma • metastases

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