Triple paraneoplastic syndrome of hypercalcemia, leukocytosis and cachexia in two human tumor xenografts in nude mice.

Nude mice bearing the human oral cavity carcinoma cell line OCC-1, and the lung cancer cell line LC-1, developed a triple paraneoplastic syndrome consisting of hypercalcemia, cachexia and leukocytosis. All of these abnormalities disappeared rapidly after surgical resection of the tumors, suggesting their ectopic humoral nature. Search for the factors responsible for the respective abnormalities revealed that the production of parathyroid hormone-related protein and colony-stimulating factors (CSFs), mainly granulocyte-CSF, by the tumors could explain the hypercalcemia and leukocytosis, respectively. With regard to the severe cachexia, the production of two cachexia-associated cytokines, interleukin-6 and leukemia inhibitory factor, was able to explain the syndrome in OCC-1 bearing nude mice; however, the factor responsible in LC-1 bearing nude mice could not be identified. The triple paraneoplastic syndrome that developed in these two animal models could be explained partly by concomitant production of the peptide hormone and cytokines by cancer cells. These animal models may be very useful for the evaluation of diagnostic and therapeutic modalities for humoral abnormalities.

Frequent development of murine T-cell lymphomas with TcR alpha/beta+, CD4-/8- phenotype after implantation of human inflammatory breast cancer cells in BALB/c nude mice.

Tumors developed quite frequently in some of the visceral organs, including spleen and liver, in BALB/c nude mice upon subcutaneously xenografting surgical specimens from five different inflammatory breast cancer patients. All of these tumors developed within two and a half months to one year after the subcutaneous inoculation of surgical specimens. From these tumors, five independent transplantable tumors, including tMK-2, tHK-1, tYK-1, tYK-2 and tTY-1 have been established. Chromosome analysis, morphologic studies by light and electron microscopy and phenotype analysis indicated that these tumors are of mouse origin. The tMK-2 tumor was highly metastatic to the spleen and liver when it was subcutaneously transplanted into the right scapular region. In addition, the region where the tMK-2 tumor cells were subcutaneously inoculated showed an apparently inflammatory process represented by erythema. After subcutaneous inoculation into the right scapular region, tHK-1, tYK-1, 2, and tTY-1 tumors also metastasized to some of the visceral organs, including spleen and liver. From these tumors, in vitro cell lines were established. The cells grew in a stromal-cell dependent manner under in vitro culture conditions. The cells were again tumorigenic at the inoculated region and metastasized to various organs, including liver and spleen, of BABL/c nude mice. Histological examination revealed that the tumors showed features of malignant lymphoma. Phenotypically, these five tumors expressed early T lymphocyte markers as revealed by anti-mouse anti-TcR alpha/beta, anti-CD3, CD4 and CD8 monoclonal antibodies. To our knowledge, these cell lines are the first T-cell lines showing the phenotype of extrathymically differentiated T-cells in the liver.