Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth
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RESEARCH
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Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth Heiko Enderling, Lynn Hlatky and Philip Hahnfeldt* * Correspondence: philip. [email protected] Center of Cancer Systems Biology, Steward St. Elizabeth’s Medical Center, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135, USA
Abstract Background: The role of the immune system in tumor progression has been a subject for discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression. Methods: We implement a cellular automaton model previously described that captures the dynamical interactions between the cancer stem and non-stem cell populations of a tumor through a process of self-metastasis. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression. Results: A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response. Conclusions: Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step “immunoediting” concept – the modulation of tumor growth through inhibition, selection and promotion.
Background The immune system in mammals is responsible for elimination of damaged cells. The development of tumors is always associated with an immune response [1]. Complete activation of the adaptive immune system might result in complete tumor eradication, but tumor progression and clinical manifestation has demonstrated the ability of tumor cells to escape immunosurveillance, despite efficient immune responses. In fact, a massive influx of activated infiltrating immune cells is correlated with a poor patient prognosis, fueling the hypothesis that an immune reaction may under some circumstances be tumor-promoting [1]. The potential for a tumor-promoting action by the immune system was proposed some time ago [2], but the actual mechanisms are still the subject of debate. We do know that infiltrating macrophages and mast cells can © 2012 Enderling et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided
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