The primary tumor is the primary source of metastasis in a human melanoma/SCID model. Implications for the direct autocrine and paracrine epigenetic regulation of the metastasis process.
Although previous autopsy and experimental studies had indicated that metastases can metastasize, the question of whether metastases from metastases increasingly contribute to the overall metastatic burden is crucial to the basic question of whether the metastatic process is more directly regulated by genetic or by epigenetic mechanisms. The highly metastatic human C8161 melanoma was transfected with either pSV2neo or pSV2hygro and clones of neo-C8161 and hyg-C8161 were injected intravenously and subcutaneously in SCID mice. In combination experiments, both the timing and size of inoculum of tumor cells were titrated to ensure that the hematogenously injected cells disseminated almost exclusively to the lungs and that the overall pulmonary burden was equal to the primary tumor. In s.c. injection experiments, no spontaneous metastases ever developed when the primary tumor was extirpated before it had grown to more then 0.5 cm in diameter. When the primary tumor approached 1 cm in diameter, widely-disseminated metastases developed within lungs, liver subcutaneous sites and other internal viscera. In the combination-injection experiments, while large numbers of both hematogenously and spontaneously metastatic clones were recovered from the lungs, a vast excess of only the latter clones was recovered from extrapulmonary sites. Both hematogenously and spontaneously metastatic pulmonary clones recovered showed similar levels of Matrigel invasion and collagenases by substrate gel electrophoresis, but significantly decreased levels when compared to the cell line. Primary tumor clones, in contrast, demonstrated increased invasion and increased collagenases. Our findings argue for the importance of paracrine (orthotopic) and autocrine (size) epigenetic mechanisms in the regulation of metastasis.
Safarians
S
S
Department of Pathology, University of California, Los Angeles, CA, 90024, USA.
Sternlicht
M D
MD
Freiman
C J
CJ
Huaman
J A
JA
Barsky
S H
SH
D000818:Animals; D017364:Collagenases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics*; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D017364:Collagenases