Paradoxes in carcinogenesis: New opportunities for research directions
Paradoxes in carcinogenesis: New opportunities for research directions
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DOI：
10.1186/1471-2407-7-151
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发表时间：
2007-08-06
期刊：
影响因子：
3.8
通讯作者：
Kramer, Barnett S.
中科院分区：
文献类型：
--
作者：
Baker, Stuart G.;Kramer, Barnett S.
背景资料：癌症研究中的流行范式是体细胞突变理论，该理论认为癌症始于体细胞中的单一突变，随后是连续突变。许多癌症研究都涉及不断增加的基因变化目录来完善体细胞突变理论。问题是，这样的研究可能会错过癌发生的矛盾方面，在体细胞突变理论下没有可能的解释。这些矛盾的方面提供了新的研究方向，不应被忽视的机会。讨论：各种悖论相关的体细胞突变理论的致癌作用进行了讨论：（1）在促进开始时存在大量空间上不同的癌前病变，（2）在不被认为是癌症的增生性息肉中发现大量遗传不稳定性，（3）自发消退，（4）着色性干皮病患者的癌症发病率较高，但在DNA修复中有其他类似缺陷的患者中则不然，（5）唐氏综合征患者中除白血病和睾丸癌外，许多癌症的发病率较低，（6）正常组织移植到身体其他部位或先前暴露于致癌物质的基质附近后发生癌症，（7）当暴露于致癌物的上皮细胞被移植到正常基质附近时，没有肿瘤;（8）当将各种孔径的微孔过滤器插入大鼠皮肤下时，只有在孔足够小的情况下，才有癌症的发展。对于后一个悖论，提出了一个微阵列实验，试图更好地理解现象。摘要：著名物理学家尼尔斯·玻尔说：“我们遇到了一个悖论，这是多么美妙。现在我们有了取得进展的希望。“同样的观点也适用于癌症研究。我们很容易忽视这条关于促进知识发展的智慧，但我们这样做是有风险的。
Background: The prevailing paradigm in cancer research is the somatic mutation theory that posits that cancer begins with a single mutation in a somatic cell followed by successive mutations. Much cancer research involves refining the somatic mutation theory with an ever increasing catalog of genetic changes. The problem is that such research may miss paradoxical aspects of carcinogenesis for which there is no likely explanation under the somatic mutation theory. These paradoxical aspects offer opportunities for new research directions that should not be ignored.Discussion: Various paradoxes related to the somatic mutation theory of carcinogenesis are discussed: (1) the presence of large numbers of spatially distinct precancerous lesions at the onset of promotion, (2) the large number of genetic instabilities found in hyperplastic polyps not considered cancer, (3) spontaneous regression, (4) higher incidence of cancer in patients with xeroderma pigmentosa but not in patients with other comparable defects in DNA repair, (5) lower incidence of many cancers except leukemia and testicular cancer in patients with Down's syndrome, (6) cancer developing after normal tissue is transplanted to other parts of the body or next to stroma previously exposed to carcinogens, (7) the lack of tumors when epithelial cells exposed to a carcinogen were transplanted next to normal stroma, (8) the development of cancers when Millipore filters of various pore sizes were was inserted under the skin of rats, but only if the holes were sufficiently small. For the latter paradox, a microarray experiment is proposed to try to better understand the phenomena.Summary: The famous physicist Niels Bohr said "How wonderful that we have met with a paradox. Now we have some hope of making progress." The same viewpoint should apply to cancer research. It is easy to ignore this piece of wisdom about the means to advance knowledge, but we do so at our peril.