Friday, October 10, 2008

Neoplasms: Excerpt 4

Neoplasms: principles of development and diversity was published October 1, 2008. In the next few blogs, I will provide some short excerpts from the book.

Excerpt from Chapter 2 Carcinogenesis (Section 2.8: Latency):

The latency period is the time between exposure to a carcinogen (the initiating event) and the emergence of a detectable neoplasm. The latency period is one of the least understood aspects of carcinogenesis.

We know that in some experimental systems, after initiation, the initiated cells look like normal cells and can participate in normal differentiation. Gestl and coworkers used a transgenic mouse strain containing the Wnt oncogene, but in which Wnt expression is doxycycline dependent (30). These transgenic mice, when provided with doxycycline in their diet, will almost always develop Wnt-initiated mammary adenocarcinomas.

In this system, the process of postinitiation carcinogenesis can be interrupted by simply withdrawing doxycycline from the diet of the mice. Initiated mammary tissue can be transplanted into cleared fat pads of uninitiated transgenic mice (that have not had doxycycline in their diets) and then observed. The initiated mammary tissue, now growing without the influence of the Wnt oncogene, grows as normal mammary explants, producing ducts and lobules that are indistinguishable from the ducts and lobules of normal mammary tissue. If doxycycline is added to the diet of the mice receiving the transplants, the initiated tissue resumes its carcinogenic pathway to quickly yield multiple synchronous carcinomas. This tells us that initiated cells can look and behave like normal cells, under experimental conditions. Because tumors arose rapidly after doxycycline-dependent Wnt expression was restored, it suggests that the growth of initiated (but latent) cancer foci can be manipulated. This means that we may be able to develop new therapeutic interventions that stop the growth of latent cancers.

Currently, nobody knows all the conditions that lengthen or shorten the latency period. Because carcinogenesis is a multistep process, we can guess that very condition that modifies early steps in carcinogenesis will have some effect on the latency period.

In carcinogenesis experiments, we can expose a large number of rodents of a single strain, gender, and age to a single carcinogen at the same dose. In the 1970s, cancer researchers used this approach to investigate whether the initiating dose of a carcinogen would modify the latency period. Specifically, they wanted to determine whether low doses of a carcinogen would result in a latency period that exceeded the life expectancy of the animal. If this were the case, there would be no practical problem with exposing animals (or people) to doses of carcinogen that produce a longer-thanlifetime latency.

Many rodent trials ensued. Latency was measured as the time between initiation and the time that the first tumor occurred. It is not surprising that high doses of carcinogen produced short latency periods. Low doses of carcinogen resulted in long latency periods. Very low doses of carcinogen produced very long latency periods. Extremely low doses of carcinogens usually produced no more tumors than no carcinogen at all.

In a mathematical analysis conducted in 1977,Guess and Hoel showed that these prior measurements of tumor latency were simply manifestations of dose-dependent changes in tumor incidence. If a high-dose drug produces many more tumors than a low-dose drug, and if the tumor latency period is random (i.e., not determined by the dose of drug), you would see that tumors occurred earlier in the high-dose subjects.Why? The more tumors that occur, the likelier it would be that some tumors will occur early rather than late. If a low-dose carcinogen produces very few tumors, the time before the first tumor develops will likely be longer, simply because there are fewer tumors (31). Today, low-dose risk extrapolations take into account dose-dependent changes in tumor incidence.

Despite decades of research, tumor latency remains one of the murkiest areas of carcinogenesis.We do not know whether there is a safe dose for carcinogen exposure.

(to be continued)

The full table of contents is available. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic
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