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

Abstract

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 orthotyrosine 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. Cancer Res; 72(5);

Roles of the tyrosine isomers meta- tyrosine and ortho- tyrosine in oxidative stress

“…Two reports have independently observed a reduction in the levels of phosphorylated ERK and STAT proteins following the treatment of cells with the tyrosine isomers. Ruggiero et al showed lymphoma cells cultured in media with m -tyrosine (1.38 mM) had significantly reduced levels of phosphorylated ERK1/2 and STAT3 compared to controls, and the addition of phenylalanine counteracted these results (Ruggiero et al, 2012). Mikolás et al reported similar results when TF-1 erythroblasts were incubated with either m - or o -tyrosine (110 μM).…”

Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review

“…In fact, m-Tyr inhibited both MAPK/Erk- as well as STAT-signaling, and decreased the expression of Ki-67 protein, indicating that these tumor cells moved into the G0 cell cycle phase [85]. Further data of the workgroup suggest that other signaling proteins such c-myc, BCL-XL or Cyclin-D may be involved [86]. Also, exogenous, periodic iv.…”

“…However, the mechanism of concomitant tumor resistance may be somewhat different, as addition of specific amino acids, such as phenylalanine, glutamate, aspartate, glutamine or histidine could lead to a reversal of tumor-inhibition. This seems to explain also, why m- and o-Tyr only inhibit growth of the second cancer or metastases not the primary tumor, as these amino acids were proven to accumulate in the primary tumor but not the metastases [85,86]. …”

Incorporation of Ortho- and Meta-Tyrosine Into Cellular Proteins Leads to Erythropoietin-Resistance in an Erythroid Cell Line

“…Ehrlich observed in 1906 the phenomenon, known as concomitant tumor resistance, where a tumor-bearing host inhibits the growth of secondary tumor implants or metastasis. Ruggiero et al identified the active serum fraction responsible for this phenomenon containing a mixture of the three isoforms of tyrosine [17]. According to their in vitro and in vivo studies ortho- and meta-tyrosine inhibits tumor growth in a dose dependent manner.…”