Concomitant
tumor resistance (CR) is a phenomenon in which a
tumor-bearing host is resistant to the growth of secondary
tumor implants and
metastasis. Although previous studies 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 a recently published study, we identified this factor as
meta-tyrosine and
ortho-tyrosine, 2 isomers of
tyrosine that would not be present in normal
proteins. In 3 different murine models of
cancer that generate CR, both meta- and
ortho-tyrosine inhibited
tumor growth. Additionally, 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 isomers were mediated in part by early inhibition of the MAP/ERK pathway and inactivation of STAT3, potentially driving
tumor cells into a state of dormancy in G(0)-phase. Other mechanisms, putatively involving the activation of an intra-S-phase checkpoint, would also inhibit
tumor proliferation by accumulating cells in S-phase. 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 or after other stressors that may promote the escape of
metastases from dormancy, an issue that is of pivotal importance to oncologists and their patients.