Aberrations, tumor

As already described in Sects. 15.2 and 15.3, immunotherapy is heavily hampered by the morphologically aberrant tumor microvasculature and increased interstitial fluid pressure, which can impede the delivery of cytokines and monoclonal antibodies and can prevent immigration of immune effector cells into the established tumor parenchyma. 

Recoverin is aberrantly expressed in malignant tumors localized outside the nervous system. This was found to trigger the immune system resulting in the production of autoantibodies inducing the degeneration of the retina. 

Besides the cytokine receptors that lack intrinsic kinase activity but have associated JAK kinases, STAT proteins can be activated by a variety of G-protein coupled receptors and growth factor receptors with intrinsic tyrosine kinase activity (for example EGF, PDGF, CSF-1, and angiotensin receptor). Increasing evidence suggests a critical role for STAT family members in oncogenesis and aberrant cell proliferation. Constitutively activated STATs have been found in many transformed cell lines and a wide variety of human tumor entities. Numerous non-receptor tyrosine kinases and viral oncoproteins, such as v-Src, v-Abl, v-Sis, and v-Eyk, have been identified to induce DNA-binding activity of STAT proteins. 

The recent links made between mTORCl and tumor suppressors/oncoproteins suggests that aberrantly high mTORCl activity may be the underlying cause of hamartomas and perhaps some cancers. Based on this, many clinical trials are underway to determine the efficacy of rapalogs as anti-cancer agents. Current phase III clinical trials include ... 

VERGHESE M, RAO D R, CHAWAN C B, WILLIAMS L L, SHACKELFORD L (2002) Dietary inului suppresses azoxymethane-induced aberrant crypt foci and colon tumors at the promotion stage in young fisher 344 rats. J. Nutr. 132 2809-2813. 

Nitro PAHs have been shown to exhibit a large variety of biological activities. Included in these are the induction of mutations in bacterial (Table I) and eukaryotic cells (9,17,54-57), the neoplastic transformation of cultured mammalian cells (58-59), and the induction of DNA strand breaks (60), DNA repair (61-62), sister chromatid exchanges (63-64), and chromosomal aberrations (65-66). Nitro PAHs have also been demonstrated to bind cellular DNA in bacteria (67-73) and mammalian cells (74-77), to inhibit preferentially the growth of repair-deficient bacteria (78), to have recombinogenic activity in yeast (66,79-80) and to induce tumors in experimental animals (Table II). 

Structural and numerical chromosomal aberrations in somatic cells may be involved in the etiology of neoplasia and in germ cells can lead to perinatal mortality, dominant lethality or congenital malformations in the offspring (Chandley, 1981), and some tumors (Anderson, 1990). 

As indicated above in the section on "Genotoxic Effects", it is likely that mirex and chlordecone are tumor promoters and not tumor initiators. Initiators irreversibly alter DNA by a mutation, chromosomal aberration, or other alteration. Promoters act by facilitating the proliferation of previously initiated preneoplastic cells. One of the mechanisms for promotion is believed to involve suppression of inhibitory proliferative control through inhibition of gap-junctional-mediated intercellular communication as well as enzyme induction (Trosko et al. 1983). The results of studies to evaluate the promotional activity potential of mirex in mice indicate that mirex is a mouse skin cancer promoter but exerts this toxicity through a hitherto unknown mechanism that is different from that of phorbol esters, such as TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). Unlike initiation, promotion is a reversible process to a point. This implies, at least in theory, that there may be justification for setting NOAELs for promoters. 

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