Chapter 12: Tumor Growth, Microenvironment, Metabolism, and Hypoxia

12.1 TUMOR GROWTH AND CELL KINETICS

Tumors grow because the homeostatic mechanisms that maintain the appropriate number of cells in normal tissues are defective, leading to an imbalance between cell proliferation and cell death and to expansion of the cell population. Methods based on autoradiography with tritiated thymidine in the 1950s and 1960s, and the subsequent application of flow cytometry, have allowed a detailed analysis of tumor growth in terms of the kinetics of proliferation of the constituent cells. The proliferative rate of tumor cells varies widely between tumors; slowly proliferating or nonproliferating cells are common, and there is often a high rate of cell death.

12.1.1 Growth of Human Tumors

Because tumors are generally treated rather than observed, most of the data on growth rates of untreated human cancers are from studies undertaken before the development of effective therapies. Accurate measurements could be made only on tumors from selected sites, and most studies have examined either superficial tumors (eg, those in the skin or breast) or lung metastases using serial chest radiographs. Because there is a limited observation period between the time of tumor detection and either death of the host or initiation of therapy, such measurements represent only a small fraction of the history of the tumor’s growth (see Fig. 12–1).

Despite these limitations, Steel (1977) was able to review measurements of the rate of growth of more than 600 human tumors, with the following general conclusions:

1. There is wide variation in growth rate, even among tumors of the same histologic type and site of origin.

2. Childhood tumors and adult tumors that are known to be responsive to chemotherapy (eg, lymphoma, cancer of the testis) tend to grow more rapidly than less-responsive tumors.

3. Over a limited period of observation, the time for the tumor volume to double was often constant, implying exponential growth. Doubling times for lung metastases of common tumors in humans were in the range of 2 to 3 months.

Exponential growth of tumors will occur if the rates of cell production and of cell loss or death are proportional to the number of cells present in the population. Exponential growth often leads to the false impression that tumor growth is accelerating with time (see Fig. 12–1). Increase in the diameter of a human tumor from 0.5 to 1.0 cm may escape detection, whereas an increase from 5 to 10 cm is dramatic and is likely to cause new clinical symptoms. Both require 3 volume doublings, and during exponential growth, they will occur over the same period ...