EDITORIAL OPINION
The importance of adaptive response in cancer prevention and therapy
There has been a considerable amount of progress in our understanding of cancer biology in the past several decades, with the improved knowledge leading to the development of therapies designed to interrupt the carcinogenic process. For example, the importance of angiogenesis for tumor growth was recognized in the 1970s leading to the development of treatments with anti-angiogenesis agents.1 Preclinical studies have shown the effectiveness of such agents in slowing the growth of tumors,2 but the adaptive response to the antiangiogenesis therapy also tended to make the tumors more invasive.3 Patient studies have shown limited success in reducing tumor growth using antiangiogenesis therapies.4 One disadvantage of such therapies reported in some studies is that when the antiangiogenesis treatment was stopped for any reason, the tumor growth became more aggressive,5, 6 possibly because of the adaptive response of upregulation of other proangiogenesis factors in the tumor in response to the therapy.4, 7 Thus, ignoring the effect of adaptive response may have been counter-productive, though the treatment method was thought to be well-justified based on knowledge of the carcinogenic process. Another example that demonstrates the apparent importance of adaptive response in the carcinogenic process is the reported occasional inhibition of distant untreated tumors through immune stimulation following radiation therapy to a tumor, known as the abscopal effect.8–13 Since high dose radiation is known to suppress the immune system14 and low dose radiation is known to elevate it,15, 16 the observed immune stimulation is most likely to be from the adaptive response in the parts of the body incidentally exposed to low dose radiation during the radiation therapy. Fractionated radiotherapy was found to elicit the abscopal effect in a preclinical model but not single dose radiotherapy,17 again suggesting the importance of lower radiation doses for activating the abscopal effect. The contrast between these two observations is striking. In spite of the antiangiogenesis therapy being based on the known importance of angiogenesis for tumor growth and the factors influencing angiogenesis, ultimately the therapy resulted in more aggressive tumors in some patients because of not taking into account the adaptive response of the tumors. In the case of the abscopal effect, in spite of not targeting the tumors away from the treatment site, the adaptive response of increased immune function due to incidental and unintended low dose radiation to parts of the body apparently eliminated the metastatic tumors. These two results demonstrate the potential importance of including adaptive response in our considerations when estimating biological effects of external agents. 030401-1
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The immune origin of the abscopal effect also suggests that elevation of the immune system response from total body or half body low dose radiation16 may be useful in arresting the carcinogenic process in patients that have been diagnosed with early stage cancer in screening programs, such as for breast cancer, without the need for invasive lumpectomy procedures. Low dose radiation could also be potentially useful for breast cancer patients following lumpectomy to eliminate any residual microscopic lesions. Low dose radiation may eliminate these cancers without any side effects as compared to sometimes serious side effects of radiation therapy or chemotherapy that may be prescribed for such patients. Interspersing low dose whole body radiation between high dose radiation treatments to the tumors could potentially provide more effective tumor control through stimulation of the immune system as has been shown in preclinical18 and clinical studies.16 Low dose radiation may also be helpful to reduce cancers in population groups that have been exposed to high dose radiation, e.g., atomic bomb survivors or Chernobyl workers, by boosting their immune system. Clinical trials would be needed to confirm the effectiveness of low dose radiation in all these applications. If low dose radiation is found to be effective in reducing cancers in such clinical trials, testing of the concept in the general public to reduce cancer incidence may be justified, as has been proposed before.19, 20 Since the increased immune system response from low dose radiation is immediate, whereas the carcinogenic effect of high dose radiation has a lag time of several years to manifest, the standard practice of epidemiological studies of only considering cancers occurring after a lag time of several years following acute radiation exposure would result in ignoring the short term reduction in cancers expected from the adaptive response to low dose radiation. Hence, the conclusions of epidemiological studies that have used such a lag time for low dose radiation may be questionable, since they would exaggerate the risks of low dose radiation. Since such studies have been used to justify the use of the linear no-threshold (LNT) model, the validity of LNT model may also be questionable. Another reason to question the validity of the LNT model is that it completely ignores adaptive response to low dose radiation that we have seen may be important for determining biological effects of external stimuli. In view of the above considerations, a paradigm shift may be advisable in radiation safety from the present one based on the LNT model, to one that recognizes the presence of a beneficial adaptive response from low dose radiation, as has been recommended before.21–23 Scientific and professional organizations and journals can play a major role in facilitating this by recognizing the importance of adaptive response and supporting the change in the radiation safety paradigm. This
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Mohan Doss: Importance of adaptive response in cancer therapy
could help to enable the clinical trials for cancer prevention and therapy using low dose radiation. Governments have generally been guided by the recommendations of advisory organizations in setting radiation protection policies in the past because of the perceived complex nature of biological effects of low dose radiation. However, the simple arguments presented above for the importance of adaptive response should influence the recommendations of such organizations. In summary, the two observations, (i) the ultimately counter-productive effect of some antiangiogenesis therapies because of ignoring adaptive response of tumor cells, and (ii) the effectiveness of incidental adaptive response (enhanced immune response due to low dose radiation to parts of the body) in eliminating untreated lesions at sites away from the high dose radiation-treated tumors, demonstrate the potential importance of considering adaptive response when estimating biological effects from external agents such as radiation. The utilization of low dose radiation adaptive response to reduce cancers, if it is found to be effective in clinical trials, could be a major improvement to present treatments using high dose radiation or chemotherapy which can have serious adverse side effects. A paradigm shift in radiation safety may be advisable that recognizes the importance of low dose radiation adaptive response to enable the use of low dose radiation for cancer prevention and therapy. ACKNOWLEDGMENTS Thank to Dr. J. Q. Yu, Dr. R. K. Alpaugh, and Dr. M. K. Robinson for helpful comments for a draft of the paper. This work was supported in part by the Office of Science (BER), U.S. Department of Energy, under Award No. DESC0001196. 1 J. Folkman, “Anti-angiogenesis: New concept for therapy of solid tumors,”
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Mohan Doss Diagnostic Imaging, Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111 e-mail: mohan.doss@fccc.edu