Carcinogenesis multistep

Land, H., Parada, L.F., and Weinberg, R.A. (1983a). Cellular oncogenes and multistep carcinogenesis, Science 222,771. 

The myc Gene Product The jun and fos Gene Products The Transition from Protooncogene to Oncogene Carcinogenesis Is a Multistep Process... 

One further comment on the multistep nature of carcinogenesis In our discussion here, we focused on some of the early steps in the process that lead to uncontrolled growth but said nothing about those transitions that convert transformed cells into invasive cells. We also concentrated on oncogenes related to cancer-causing viruses because these are most likely to be the first understood in terms of their biochemical function. 

Brouland, J. P., Gelebart, P., Kovacs, T., Enouf, J., Grossmann, J. and Papp, B., 2005, The loss of sarco/endoplasmic reticulum calcium transport ATPase 3 expression is an early event during the multistep process of colon carcinogenesis. Am J Pathol 167, 233-42. 

It has been established that the pathological processes of multistep carcinogenesis comprises initiation, promotion, and progression. The natural history of carcinogenesis and cancer provides a strong rationale for a preventive approach to the control of this disease and leads one to consider the possibility of active pharmacological intervention to arrest or reverse the process of carcinogenesis before invasion and metastasis occur. Such intervention is called chemoprevention. Tss... 

Barrett JC. 1993. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ Health Perspect 100(4) 9-20, 109. 

Figure 5 Multistep aspects of human colon carcinogenesis.

Weinberg, R. A. (1989). Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. 

Use of this proposed approach represents a significant paradigm shift in noncancer risk assessment and is inconsistent with basic biological principles. Earlier in this chapter we discussed the fact that it is unlikely for many carcinogens to operate with a linear dose-response. Although it is possible for a single molecule to interact with DNA to increase cancer risk, carcinogenesis is not a multistep process, and protective controls are in place to limit tumor formation. 

Fig. 2 Cumulative risk of CRC among gene carriers in HNPCC. The gene carriers cumulative risk of CRC increases as an almost perfectly linear function of time above the third decade of life, with a CRC risk of 1.6% per year. This linear relationship does not fit the classical multistep model of carcinogenesis, but is compatible with a one-hit model of carcinogenesis. (Redrawn with the data of Voskuil et al., 1997.)...

Instead of trying to test the model by demonstrating the existence of facts predicted by the theory, one could also follow the reverse pathway and try to find out whether the few-hits-and-run model could explain findings that cannot be satisfactorily interpreted in the frame of the multistep model (with the associated classical concepts of initiation and promotion). Flagrant violations of the classical model of carcinogenesis have been reported in the literature about experimental models of chemically induced CRCs and other cancers. 

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