Tumor cells heterogeneity

Poste, G., Tzeng, J., Doll, J., Greig, R., Rieman, D. and Zeldman, I. (1982), Evolution of tumor cell heterogeneity during progressive growth of individual lung metastases. Proc. Natl. Acad. Sci. USA 79, 6574-6578. 

Poste, G., Fidler, I. J. Therapeutic amplification of macrophage-mediated destruction of tumor cells, an approach to cancer chemotherapy that addresses the problem of tumor cell heterogeneity, in Design of Models for Testing Cancer Therapeutic Agents (eds.) Fidler, I. J., White, R. J., p. 225, New York, Van Nostrand Reinhold 1982... 

Fig. 1. Microenvironmental factors and the invasive process. The primary tumor is a heterogeneous mix of cell populations, further diversified by gradients of blood-borne nutrients, oxygen, and drugs. Hypoxia contributes to treatment resistance, upregulates pro-angiogenic and pro-invasive molecules, and helps to maintain cancer stem-like cell populations. Tumor cells may undergo epithelial-to-mesenchymal transition (EMT), enter blood vessels, and disseminate to distant sites where they extravasate, invade, and colonize the tissues. Once established, the cells may undergo the reverse program (mesen-chymal-to-epithelial transition, MET) and proliferate to form metastases, the major reason for treatment failure.

Drugs that act by different mechanisms may have additive or synergistic therapeutic effects. Tumors may contain heterogeneous clones of cells that differ in their susceptibility to drugs. Combination therapy will thus increase log cell kill and diminish the probability of emergence of resistant clones of tumor cells. 

Many of the anti-neoplastic drugs currently available on the market specifically target the cancerous tumor and do not account for the overall heterogeneity of the disease. It is reasonable to assume that due to the complex make-up of a tumor, combined therapies may be necessary to treat the different cell types involved. One major hurdle to understanding tumor cells at the gene expression level is our limited ability to isolate pure populations of diseased cells. 

Tumor heterogeneity refers to the existence of distinct subpopulations of tumor cells with specific characteristics within a single neoplasm. Breast cancer is a classic example of a heterogeneous disease. First, the term breast cancer does not itself refer to a single disease. Breast cancers include many different diseases including (but not limited to) adenomas, papillomas, invasive ductal carcinoma, ductal carcinoma in situ (DCIS), and lobular carcinoma in situ (LCIS) (6). 

Konemann, S., Schuck, A., Malath, J., Rupek, T., Horn, K., Baumann, M., Vormoor, J., Rube, C., and Willich, N. 2000. Cell heterogeneity and subpopulations in solid tumors characterized by simultaneous immunophenotyping and DNA content analysis. Cytometry 41 172-177. 

Figure 20.3 Heterogeneous distribution of liposomes in tumor tissues. Human colon adenocarcinoma cells (LS174T) were transplanted in dorsal skinfold chambers in severe combined immunodeficient mice. Fifteen to 32 days post tumor cell transplantation, fluorescently labeled liposomes were injected intravenously. The photos were taken at two days post injections. Liposomes accumulated only in perivascular regions in solid tumors. The arrows indicate liposomes internalized by cells. Iiar=100um. Reproduced with permission (Yuan etal., 1994).

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