Abstract

Natural Selection and Early Changes of Phenotype of Tumor Cells in vivo: Acquisition of New Defense Mechanisms

G. I. Deichman

Institute of Carcinogenesis, Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoe Shosse 24, Moscow, 115478 Russia; fax: (095) 324-1205; E-mail: antitum@space.ru

Received October 5, 1999
This review summarizes results obtained in the author's and collaborating laboratories within the last decade and is designed to attract the attention of researchers to discrete biochemical mechanisms of protection acquired in vivo by cells of malignant tumors against effectors of innate antitumor immunity. Tumor progression in vivo is associated with the appearance and selection of tumor cells with new specific characteristics: a high level of H₂O₂-catabolizing (antioxidant) activity (H₂O₂^CA) and the ability for immediate release of E₂-type prostaglandin (PGE^S) on contact with natural killers, macrophages, and neutrophils; the expression of the [H₂O₂^CA + PGE^S] phenotype provides the tumor cells with two mechanisms of local protection against effectors of innate and acquired antitumor immunity. This results in a 10-100-fold less effective rejection of tumor cells in immune and normal animals and corresponding increase of tumorigenicity. The in vitro transformation of normal fibroblasts, spontaneous or induced by oncogenes LTSV40, E1a,b, Ha-ras, myc, and also by p53¹⁷⁵ and bcl-2 does not result in the [H₂O₂^CA + PGE^S] phenotype expression, but during subsequent in vivo growth of the above-mentioned transformants the selection of tumor cells of the [H₂O₂^CA + PGE^S] phenotype is correlated with a 30-200-fold increase in their tumorigenicity (accompanied or not accompanied by spontaneous metastatic activity). Unlike the transformation induced by the above-mentioned oncogenes, the transformation of normal cells by the v-src gene results in the [H₂O₂^CA + PGE^S] phenotype expression. The data presented confirm the determining role of the v-src gene in the expression of the [H₂O₂^CA + PGE^S] phenotype. In various primary viral carcinogenesis (SV40, SA7(C8)) the natural selection of cells expressing the [H₂O₂^CA + PGE^S] phenotype begins even within the latent period and can be completed by the appearance of primary tumors.
KEY WORDS: transformation, carcinogenesis, in vivo tumor progression, antioxidant and PGE₂-releasing activity of tumor cells, protection mechanisms of tumor cells, innate and specific antitumor immunity