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

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.

The acceleration of metastases after tumor removal and the paradoxical phenomenon of concomitant tumor resistance

“…For the last 30 years, we have studied, in our laboratory, the phenomenon of CR associated with the growth of many murine and human tumors (the latter growing into immune-deficient mice) in an attempt to integrate the different hypotheses into a coherent picture. Our results, summarized in Table 1 and reported, at least in part, in former papers [17,45,49,59,73,76,77] demonstrated that, two main temporally separate peaks or events of CR are generated during primary tumor growth. The first peak was only induced by immunogenic tumors of small size (≤ 500 mm 3 ); it was tumor-specific and thymus-dependent as it was exhibited in euthymic but not in nude mice, its intensity was proportional to tumor immunogenicity and a typical immunological rejection -associated with extensive necrosis and a profuse infiltration with polymorphonuclear granulocytes and mononuclear cells was observed histologically at the site of the second tumor implant undergoing CR.…”

“…In these experiments, either immunogenic or nonimmunogenic murine tumors, as well as human tumors growing in immune-deficient mice were used. These experiments suggested that a primary tumor can restrain the growth of metastases that can be considered as natural secondary tumor implants developed spontaneously during the growth of a primary tumor [9,15,16,[42][43][44][45][46][47][48][49]. These experiments also demonstrated that the mechanisms of enhancement of metastases after tumor removal would not be necessarily dependent upon a previous immune restriction of the metastatic foci because the inhibition produced by the primary tumor on its metastases can be immunological, as well as non-immunological in nature.…”

“…CR was originally described by Paul Ehrlich at the turn of the 20 th century [51] but, apart from a few isolated reports [52,53] it remained virtually forgotten for about 60 years until it was re-discovered in the 60's by Southam [54], Gershon [55] and others [56,57]. Since that moment on, some groups have studied this phenomenon demonstrating that both immunogenic and non-immunogenic tumors can induce CR in different animal models such as mice, rats and hamsters [9,16,17,45,58,59]. However, even after its renascence, CR has not received much attention as compared with other areas of cancer research despite the fact that it has been directly described in human beings [54] and, as shown above, despite its putative relevance to the mechanisms of metastases control.…”

“…In recently published works [17,45], we identified the antitumor serum factors associated with CR as a rather equi-molar mixture of meta-tyrosine (m-Tyr) and ortho-tyrosine (o-tyr), two unnatural isomers of tyrosine, unnatural meaning that it is thought that they are absent from normal proteins [78,79]. We carried out this characterization starting from mice bearing a non-immunogenic murine lymphoma that produces the strongest second peak of CR among all our murine tumor models [17] and also from nude mice bearing a human prostatic carcinoma that produces the strongest CR among all the human lines tested [45]. We could demonstrate that m-tyr and o-tyr were responsible for 90% and 10%, of the total antitumor activity of the serum, respectively, as determined by the inhibition of both the in vitro proliferation of different murine and human tumor cells and the in vivo growth of subcutaneous tumor implants.…”

MicroRNA-3163 targets ADAM-17 and enhances the sensitivity of hepatocellular carcinoma cells to molecular targeted agents

“…The Notch signaling pathway is a key regulator of cellular fate, survival, and cellular stress/cellular injury responses in HCC cells 17,18 . The aberrant expression of Notch protein or activation of the Notch pathway has been reported in various malignancies, such as prostate cancer, colorectal cancer, breast cancer, and especially in HCC [19][20][21][22][23] . During clinical treatment, radiotherapy (ionizing radiation) or chemotherapeutic agents (cellular toxicity) may function as cellular injuries to HCC cells, activating Notch.…”