Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis

Geraldine Gueron,Sofía Lage Vickers ,Nicolás Anselmino ,Ariel Ramiro Strazza ,Daniela Montagna ,Javier Cotignola,Mario Contín ,Felipe M Jaworski ,Darío Leonardi ,Nora M Navone ,Roberto P Meiss ,Paula Chiarella,Raúl A Ruggiero ,Verónica E Manzano ,Norma D ́Accorso ,Anna Woloszynska‐Read ,Jimena Giudice,Emiliano G Ortiz ,Alejandra Páez ,Estefanía Labanca ,Elba S Vázquez

doi:10.1038/s41419-017-0147-8

Abstract

An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate, lung anaplastic, and nasopharyngeal carcinoma). Moreover, m-Tyr was detected in the serum of mice bearing prostate cancer (PCa) xenografts. Primary tumor growth was inhibited in animals injected with m-Tyr. Further, the CR phenomenon was reversed when secondary implants were injected into mice with phenylalanine (Phe), a protective amino acid highly present in primary tumors. PCa cells exposed to m-Tyr in vitro showed reduced cell viability, downregulated NFκB/STAT3/Notch axis, and induced autophagy; effects reversed by Phe. Strikingly, m-Tyr administration also impaired both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, and LMM3) and PCa experimental metastases. Altogether, our findings propose m-Tyr delivery as a novel approach to boost the therapeutic efficacy of the current treatment for metastasis preventing the escape from tumor dormancy.

Highlights

Concomitant tumor resistance (CR) is the phenomenon in which a tumor-bearing host inhibits the growth of secondary tumor implants
We demonstrated for the first time that the phenomenon of CR may be induced by different experimental human solid tumors growing in immunedeficient nude mice and that the kinetics of this CR paralleled the second event of CR induced by murine tumors
Surgical removal is one of the main treatments for solid tumors. It is recommended in most clinical cases, tumor removal may trigger the acceleration of regional and distant metastases. This suggests that the primary tumor could inhibit the growth of its own metastases, an event that is mimicked by the phenomenon of CR induced in experimental animal models[9]

Summary

Introduction

Concomitant tumor resistance (CR) is the phenomenon in which a tumor-bearing host inhibits the growth of secondary tumor implants. Ehrlich[1] first described it in 1906, but this phenomenon remained forgotten for about 60 years. It was demonstrated that both immunogenic and non-immunogenic tumors could induce CR in different animal models[2]. Different explanations were proposed to address CR. The immunological hypothesis detailed how the growth of a tumor triggered an anti-tumor immune response, not strong enough to impair the growth of the primary tumor, but capable of suppressing the development of the secondary tumor inoculum[5]. The CR phenomenon was observed in the absence of an immune reaction[6,7]. Non-immunological explanations included atrepsis[1]. Others implied that the production and secretion of anti-proliferative or anti-angiogenic

Methods

Results

Conclusion