Previously we have shown that a murine mammary carcinoma cell line, designated SPI, grows and metastasizes more efficiently in the mammary gland than in the subcutis. In this report, we examine the tissue specificity of this phenomenon. Our results show that SPI cells grow best in the mesenteric and ovarian fat pads and well in the mammary gland, but very poorly in the subcutis or peritoneal cavity. Massive dissemination of tumors from the ovarian and mesenteric sites occurs to the liver, spleen and diaphragm. In contrast, metastases from the mammary site occur primarily in the lung. Co-transplantation of a threshold number of SPI cells with mammary or ovarian fat fragments into the subcutis results in increased tumor growth, whereas very few tumors form in sham controls receiving no fat fragments. Removal of the ovaries of donor and recipient mice abrogates tumor growth in adipose tissue transplants. Estrogen can stimulate growth of SPI in adipose tissue sites, whereas progesterone inhibits growth. In contrast, in vivo growth of a stable metastatic variant selected from SPI cells was not inhibited by progesterone. SPI cells growing in ovarian and mesenteric fat pads showed increased expression of estrogen receptors and progesterone receptors, as well as detectable levels of epidermal-growth-factor receptors, whereas receptor levels decreased to baseline on tumors in the subcutis. The levels of estrogen-receptor mRNA reflect the corresponding functional expression of receptors; this finding suggests that the regulation of estrogen-receptor expression in this system is, at least in part, at the mRNA level. Our results are consistent with the model that adipose tissue exerts an estrogen-dependent positive regulatory effect on primary SPI tumor growth, and promotes the formation of metastases.

The extensive metastatic capacities in nude mice of variants of a human melanoma line, MeWo, were studied. BALB/c nude mice received subcutaneous implants of lung cubes impregnated in vitro with small numbers (less than 1,000) of MeWo cells as a result of previous in vitro coincubation. Such implants always resulted in lethal tumors, despite the fact that injection of dispersed 3 X 10(5) MeWo cells was normally required to obtain a tumor take. A BALB/c nude mouse that had received a MeWo lung cube implant was found to have numerous, large lung nodules 6 months after implantation. Transfer of the metastatic lung nodules to new recipients also led to the appearance of lung metastases. Cell lines established from such metastases, or from primary tumors that arose in nude mice implanted with MeWo-infiltrated cubes, showed a remarkable ability to colonize the lungs after iv injection, in contrast to the parent MeWo cells: Lungs were found to be engorged with hundreds of nodules, many, but not all, being melanotic. Widespread extrapulmonary metastases were also observed, but only after iv injection of MeWo sublines established from metastases. Karyotype analysis revealed that lung colonies established by iv cell injection had a near diploid (i.e., wild type) number of human chromosomes (mode: 44), whereas cell lines from spontaneous metastases possessed a near tetraploid number, a possible consequence of either selection or tumor progression in vivo. The results indicate that human tumor variants with unusually aggressive metastatic capabilities can be obtained in adult nude mice, similar in nature to some highly metastatic variants derived from mouse tumors (e.g., the B16 melanoma). The availability of such variants should be a valuable aid to study aspects of tumor cell heterogeneity, progression, and metastasis from a human cancer cell perspective.

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Ewing's sarcoma/primitive neuroectodermal tumor family of tumors is part of a rare group of malignant neoplasms with small round-cell morphology. We describe a 24-year-old woman who presented with non-specific back pain. A chest radiograph and magnetic resonance imaging demonstrated an extraosseous, dumbbell-shaped mass of the posterior mediastinum with extension into the spinal canal. The patient underwent a left posterolateral thoracotomy and a T3-5 laminectomy with subsequent multi-agent chemotherapy. Histopathologic examination of the tumor demonstrated sheets of primitive small round malignant cells that showed no visible differentiation. Neoplastic cells were strongly immunoreactive for CD99 and vimentin and were negative for chromogranin, synaptophysin, CD31, CD34, calcitonin, desmin, low-molecular weight cytokeratins, wide-spectrum cytokeratins, leukocyte common antigen, S-100 protein, and thyroid transcription factor-1. The neoplasm was diagnosed as a Ewing's sarcoma/primitive neuroectodermal tumor, and cytogenetic studies confirmed a t(11;22)(q24;q12) chromosomal translocation and an associated trisomy of chromosome 2, supporting the histologic diagnosis. Extraskeletal Ewing's sarcoma/primitive neuroectodermal tumors are rare neoplasms that should be distinguished from other small round-cell tumors by morphology and ancillary laboratory techniques. Although rare, they need to be considered in the differential diagnosis of primary mediastinal tumors.