Concomitant
tumor resistance (CR) is a phenomenon originally described in 1906 in which a
tumor-bearing host is resistant to the growth of secondary
tumor implants and
metastasis. Although recent studies have indicated that T-cell-dependent processes mediate CR in hosts bearing immunogenic small
tumors, manifestations of CR induced by immunogenic and nonimmunogenic large
tumors have been associated with an elusive serum factor. In this study, we identify this serum factor as
tyrosine in its meta and ortho
isoforms. In three different murine models of
cancer that generate CR, both
meta-tyrosine and
ortho-tyrosine inhibited
tumor growth. In addition, we showed that both
isoforms of
tyrosine blocked
metastasis in a fourth model that does not generate CR but is sensitive to CR induced by other
tumors. Mechanistic studies showed that the antitumor effects of the
tyrosine isoforms were mediated, in part, by early inhibition of
mitogen-activated
protein/
extracellular signal-regulated kinase pathway and inactivation of STAT3, potentially driving
tumor cells into a state of dormancy. By revealing a molecular basis for the classical phenomenon of CR, our findings may stimulate new generalized approaches to limit the development of
metastases that arise after resection of primary
tumors, an issue of pivotal importance to oncologists and their patients.