cAMP metabolism in B16 melanoma clones during the formation of experimental and spontaneous metastases

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Abstract
The ability of B16 melanoma clones to form tumor colonies in the lung after i.v. injection (experimental metastases) correlates positively with their capacity to respond to activators of cyclic adenosine 3‐, 5‐ monophosphate (cAMP) metabolism (such as melano‐ cyte‐stimulating hormone and forskolin). To investigate whether this relationship is causal, the cAMP responses of 4 B16 melanoma clones of differing colonizing potential have been examined in freshly established stock cell cultures, in pulmonary colonies in vivo and in cultures established from these lesions. In all cases, the cAMP responsiveness of the excised colonies (and cultures derived from them) mimicked the responsiveness of the cultures from which they arose. B16 clones exhibiting low cAMP responsiveness gave rise to few experimental metastases all of which were poorly responsive to activators of cAMP metabolism. Similarly, clones with high cAMP responsiveness formed multiple lung colonies which displayed a marked sensitivity to agents that stimulated cAMP production. Parallel experiments on the spontaneous metastatic behavior of the same clones revealed that the cAMP responsiveness of cells in the primary (intra‐ footpad) tumor and spontaneous metastatic lesions in the lung faithfully reflected the response profile of the original tumor‐cell inoculum but no correlation was found between cAMP responsiveness and the capacity to form spontaneous metastases. These data suggest that cAMP‐dependent events may influence the survival, arrest and organ colony formation by cells injected directly into the circulation but appear to be of little or no importance in determining the early event(s) involved in the evolution of spontaneous metastases prior to the entry of cells into the circulation.