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ScienceWeek
MEDICAL BIOLOGY: ON CANCER AS A ROBUST SYSTEM
The following points are made by Hiroaki Kitano (Nature 2003 426:125):
1) Cancer is an extremely complex and heterogeneous disease that exhibits a high level of robustness against a range of therapeutic efforts. Robustness enables a system to maintain functionality in the face of various external and internal perturbations. Robustness is not an accidental property, but follows certain principles. It allows tumors to promote growth and survival in several ways. For example, heterogeneity among tumour cells provides a high level of redundancy, and hence increased chances of survival and growth; these benefits are further enhanced by feedback controls at the cellular level. Viewing cancer as a robust system may provide insight for the development of new drugs and therapies.
2) In general, carcinomas are heterogeneous and intrinsically redundant populations of cells, generated by transformations including diverse mutations in individual genes, mitotic recombinations, and the loss or gain of entire chromosomes (aneuploidy). This heterogeneous redundancy makes a tumour robust, because survival of any of these proliferating tumour cells allows the cancer to recur. Unfortunately, many anti-tumour drugs are mutagens, and so the diversity of mutations may be increased among surviving cells. In order to control this robustness, an effective therapy needs to reduce or at least avoid increasing this diversity.
3) This principle has a series of implications. As we are now beginning to understand the possible causes of heterogeneity of tumour cells, the obvious thing to do would be to avoid drugs that may increase heterogeneity by triggering further mutations or aneuploidy. The appropriate strategy will depend on the level of heterogeneity and on the drugs available. When the degree of heterogeneity is low, such as in early-stage, non-solid tumors, it would be best to avoid broad-spectrum cytotoxic drugs that may increase heterogeneity, and instead look for one that targets a specific molecule (for example, ABL protein for chronic myelogenous leukemia). When the level of heterogeneity is high, there is a choice of two strategies. The first is to find a method that actively reduces diversity of mutation among tumour cells -- possibly by eliminating all tumour cells except those with a certain mutation or cellular state -- then using a drug that specifically targets cells with this property. The alternative would be to guide the malignant cells into dormancy and slow regression -- rather than acute and dramatic regressions that impose selective pressures -- so that heterogeneity does not increase. However, the drugs used to induce dormancy must be carefully selected, as cytotoxic drugs might cause further mutations, resulting in an increase in heterogeneity despite dormancy, making resistance inevitable.
4) At the cellular level, feedback control enhances robustness against possible therapeutic efforts. This control, which protects normal cells by making them robust against perturbations, is an obstacle to tumour therapy. Tumour cells counter chemotherapy by overexpressing proteins, such as MDR1, that pump toxic chemicals out of the cell. This simple feedback regulation leads to the acquisition of multidrug resistance. Likewise, the protective role of p53 protein -- which induces cells to undergo either apoptosis or cell-cycle arrest for DNA repair -- is reduced by over-expression of mdm2, a suppressor of p53 protein. Thus, modulation of feedback control is a natural strategy for systems-level cancer treatments.(1-3)
References (abridged):
1. Kitano, H. Nature 420, 206-210 (2002)
2. Morohashi, M. et al. J. Theor. Biol. 216, 19-30 (2002)
3. Carlson, J. M. & Doyle, J. Phys. Rev. Lett. 84, 2529-2532 (2000)
Nature http://www.nature.com/nature
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TUMOR FUNDAMENTALS
The following points are made by W.M. Becker and D.W. Deamer (citation below):
1) If the normal stability of the organization of tissues and organs is disturbed, a variety of disease states can occur. One example is a tissue in which the control of growth becomes defective, called a "tumor" or "neoplasm" (literally "new growth"). Neoplasms can be classified as benign or malignant, and the common term for the malignant tumor is cancer. The word cancer is taken from the Latin term for "crab" because early physicians noticed that certain skin cancers had a crablike appearance.
2) In almost every case, malignant tumors are "monoclonal", meaning that they develop from a single cell. The progenitor cell has undergone a permanent, heritable change that is transmitted to all its progeny, a process called the "neoplastic transformation". Clinically, the distinction between benign and malignant is based on the effect of the neoplasm on the survival of the host organism: The host can die from the effects of the malignant tumor but will survive the presence of the benign tumor.
3) At the cellular level, the most important difference is the likelihood that the tumor will spread. Benign tumors typically are encapsulated nodules of neoplastic tissue and therefore do not spread, whereas malignant tumors often spread to neighboring tissues and even other parts of the body. This spread to neighboring tissues is called "invasion"; the spreading to distant organs is called "metastasis", and the tumor nodules resident at sites distant from the parent tumor are referred to as metastases...
4) Tumors may arise from mature, differentiated cells or from mitotically active stem cell populations. Stem cells are relatively undifferentiated, mitotically active cells from which some more highly differentiated cells "stem". An example is the mitotically active hematopoietic ("blood-forming") stem cell population found in bone marrow that gives rise to red and white blood cells. The stem cells of various tissues are often designated by the suffix "-blasts". For example, neuroblasts are the mitotic stem cells for neurons; myoblasts are the stem cells for myocytes; and fibroblasts are the stem cells for fibrocyte connective tissue cells. Cancers of a stem cell may be designated by the suffix "-omas": neuroblastomas for tumors of neuroblastic origin; myelomas for tumors of myeloblasts, which are the stem cells of the granular leukocytes (white blood cells).
5) Another important element in tumor categorization is the tissue class of origin. "Carcinoma" refers to a tumor derived from an epithelial tissue, and "sarcoma" refers to a tumor derived from connective tissue. As indicated above, the hematopoietic system includes stem cell populations that grow and divide throughout life. All of these populations are subject to neoplasia: "lymphomas" are tumors of the lymphocytic lineage, "leukemias" and "myelomas" are tumors of the leukocytic system (the granulocytes, eosinophils, and basophils), and "erythroblastomas" are tumors of the red cell lineage.
Adapted from: W.M. Becker and D.W. Deamer: The World of the Cell. 2nd Edition. Benjamin/Cummings 1991. p.718. More information at: http://www.amazon.com/exec/obidos/ASIN/0805308709/scienceweek
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