Tyrosine Isomers Mediate the Classical Phenomenon of Concomitant Tumor Resistance

Abstract

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. Cancer Res; 71(22); 7113-24. Ó2011 AACR.

Concomitant Tumor Resistance: The Role of Tyrosine Isomers in the Mechanisms of Metastases Control

“…The mechanism of misincorporation into cellular proteins, claimed to be associated with long-lasting cytotoxicity effects on mammal and plant normal cells, could also be invoked to explain the short-lasting antiproliferative effects of m-and oTyr on tumor cells described in our previous work (46). Although this alternative is possible, some of their antitumor effects might start before such a misincorporation in proteins has a chance to occur.…”

“…In a recent study of mice bearing a nonimmunogenic lymphoma (called LB) that produced the strongest second peak of CR of all of our tumor models, we reported the origin, isolation, and identification of the serum factor(s) associated with the phenomenon of CR (46). We also reported its biological antitumor activity and the putative mechanisms of tumor inhibition.…”

“…However, it was recently suggested that oxidized amino acids, such as m-and o-Tyr, may also be generated from free amino acids that subsequently could be incorporated into proteins during synthesis (48,49). We previously observed that the serum antitumor activity attributed to m-and o-Tyr was strongly inhibited by agents that reduced the number of myeloid-derived suppressor cells (MDSC) and oxidative damage, and that in tumor-bearing mice (including the LB tumor model used in this work) and some cancer patients, MDSCs that produced large amounts of reactive oxygen species accumulated progressively in circulation (46,(50)(51)(52)(53). On the basis of these results, we suggested that free m-and o-Tyr present in the serum from tumor-bearing mice will be produced, at least in part, when circulating molecules of Phe are oxidized by hydroxyl radicals released by MDSC.…”

“…The intriguing observation that regeneration of normal tissues is usually not affected in tumor-bearing mice that exhibit the second peak of CR (43,46) might also be explained by assuming that these regenerating tissues, but not secondary tumor implants, display a content of amino acids high enough to counteract the inhibitory effects produced by m-and o-Tyr.…”

“…We suggest that downregulation of the expression of several genes engaged with cell proliferation and survival that are targets of STAT3, such as BCL-XL (B-cell lymphoma XL), cyclin D1, survivin, and myc, among others, might induce tumor cells to enter into G 0 -phase. The arrest of many tumor cells in G 0 , as revealed by the low expression of Ki-67, a protein that is expressed in G 1 -M but not in G 0 (46), is a fact and could be a consequence of the partial inactivation of STAT3. However, another feature has also been systematically associated with the inhibitory effects mediated by CR in vivo and by m-and o-Tyr in in vivo and in vitro settings: the accumulation of a fraction of tumor cells in S-phase (44,46).…”