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Cancer Robustness

© David Olle

What is robustness as it relates to cancer?

Homeostasis is a characteristic feature of complex biological systems. Homeostasis refers to the means to maintain steady state conditions within the cell by making necessary biochemical and physiological adjustments in response to changes in the environment. Normal cells as well as cancer cells utilize these processes in order to assure their survival. As a result, treatments which initially appear promising typically fail after a period of time as the cancer cells call into play alternative pathways and processes to deal with the treatment challenge. Hiroaki Kitano has described the process as a robust system, since the cancer appears hardy and vigorous. 2

What are the main features of cancer robustness?

1. Cellular heterogeneity - While normal cells are characterized by uniformity and genetic stability, the reverse is typical of cancer cells. Cancer cells develop as a result in changes in its genetic code, and these changes become more pronounced and erratic as the cancer progresses. Cell development in turn is dependent on its genetic makeup. The heterogeneous makeup of tumor cells results in the killing of cells sensitive to a chemotherapeutic drug, but the survival of less sensitive cells, which grow and proliferate. This is the hallmark of drug resistance. In addition, the cancer treatment itself may be mutagenic, resulting in an increase in heterogeneity of the tumor cells, further complicating treatment.

2. Feedback-control systems - Biochemical and physiological processes are very complex and interrelated. Changes in the quantities of one molecule, for example, result in the activation of a pathway to minimize the effect of this change. This is known as feedback-control. An example in tumor cells is the activation of multidrug-resistant 1 gene to the presence of a chemotherapeutic drug. This initiates a process that pumps the drug out of the cells. Another example is the over activation of the MDM2 gene, which causes the breakdown of p53 protein. p53 protein is a natural tumor suppressor.

What are some treatment approaches based on the robustness model?

1. Sequential drug treatments - This approach assumes that if multiple drugs are used sequentially, the cells that survive the first drug have to be vulnerable to the next drug that is used. With one group of cells removed, the remaining cells are less heterogeneous, facilitating the choice of the next drug treatment. The cancer cure cannot take place until all the heterogeneous cells of the tumor are killed. There are enormous challenges to this approach, since a quite complete genetic profile of the tumor is necessary. Recent advanced in the microarray laboratory technique promises to make this approach feasible.