Tumor-initiating cells

Mazzoleni S, Politi LS, Pala M et al (2010) Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis. Cancer Res 70 7500-7513... 

In conclusion, various studies indicate that transporters could be exploited in solid tumors when targeting tumor-initiating cells. However, there is still a significant lack of information available regarding their expression and role in these cells. In addition, to date it is still unclear which models may be most appropriate when studying these aspects in such cells. Thus, for the design of new drugs, medical... 

Liu JC, Deng T, Lehal RS, Kim J, Zacksenhaus E. Identification of tumorsphere- and tumor-initiating cells in HER2/Neu-induced mammary tumors. Cancer Res 2007 67 8671-8681. 

Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D, Medina D, Tsimelzon A, Hilsenbeck S, Green JE, Michalowska AM, Rosen JM. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res 2008 68 4674-4682. 

Li H, Chen X, Calhoun-Davis T et al. (2008) PC3 human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells. Cancer Res 68 1820-1825 Baguley BC (2006) Tumor stem cell niches a new functional framework for the action of anticancer drugs. Recent Patents Anticancer Drug Discov 1 121-127 Trumpp A, Wiestler OD (2008) Mechanisms of Disease cancer stem cells - targeting the evil twin. Nat Clin Pract Oncol 5 337-347... 

Lacerda 1, Pusztai L, Woodward WA. The role of tumor-initiating cells in drug resistance of breast cancer implications for future therapeutic approaches. Drug Resist Updat. 

In addition to the intrinsic insensitivity of the majority of tumor cells to antigrowth signals, it can be hypothesized that some tumor cells grow in the before mentioned microenvironmental insensitivity-conferring niche or represent one of the tumor-initiating cells characterized by a great self-renewal potency and a slow doubling time. 

Klaunig et al. (1991) found that hepatocyte DNA synthesis increased significantly in male mice exposed to trichloroethylene by gavage for up to 14 days, but no such increase was seen in female mice or in renal DNA synthesis in either sex. Similar exposures in rats produced increases in renal DNA synthesis in males, but no such increase in females, or in hepatic DNA synthesis in either sex. These results correlate well with observed species- and gender-specific trichloroethylene carcinogenicity, and the study authors suggest that trichloroethylene acts as a tumor promoter to induce proliferation of previously initiated cells. 

Fenvalerate inhibits intercellular communication between fibroblast cells and enhances the development of hepatocyte foci in rat liver at nonhepatotoxic dose levels. Chemicals that possess these properties are likely to be tumor promoters (Flodstrom et al. 1988). Fenvalerate alone induced no hepatotoxic effects in rat liver, as judged by transaminase activities and histology. However, some rats that were partially hepatectomized and insulted with nitrosodiethylamine — a carcinogen and tumor initiator — had significantly elevated numbers of liver foci after administrations of fenvalerate. This response suggests that fenvalerate is a potential tumor promoter (Flodstrom et al. 1988). 

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. 

The multi-hit models are most suitable for extrapolating the effect of genotoxic substances. It is implicit in these models that aU hits occur in one specific cell that only begins to divide and develop into a tumor when it has received the necessary number of hits. However, this is in poor agreement with experimental data, which show that prohferation of the cells that have had their first hit (the initiated cells) into pre-neoplastic lesions considerably increases the risk of a second hit in an initiated cell. While the one-hit model often oversimplifies the process, the multi-hit models impose an unreasonable tight restriction of the possibdity of more than one critical hit affecting the same cell. 

---