Mathematical models of tissue stem and transit target cell divisions and the risk of radiation- or smoking-associated cancer.
Mathematical models of tissue stem and transit target cell divisions and the risk of radiation- or smoking-associated cancer.
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DOI：
10.1371/journal.pcbi.1005391
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发表时间：
2017-02
影响因子：
4.3
通讯作者：
Hendry JH
中科院分区：
文献类型：
--
作者：
Little MP;Hendry JH
有令人信服的生物学数据表明，癌症是由单个靶细胞中的一系列突变引起的，导致细胞更新和分化过程中的缺陷，从而导致恶性肿瘤。由于许多诱变性损伤在细胞分裂后表达，由于细胞复制数量较多，更新较快的组织可能面临更高的风险。凯恩斯认为，通过将分裂的细胞群划分为由很少分裂的长寿干细胞和频繁分裂的短命子体运输细胞组成的谱系，更新组织可以降低癌症风险。我们开发了三个最近的癌症诱导模型，占联合维护和更新的干细胞和转运细胞，也部分转化细胞增殖和分化/凋亡的竞争过程的概括。我们特别感兴趣的是使用这些模型来分别评估与“自发”过程相关的癌症突变和发展的概率，以及与特定环境诱变剂（特别是电离辐射或吸烟）相关的癌症突变和发展的概率。所有三个模型都表明，癌症风险存在至少20个数量级的实质性差异，这取决于癌症所需的关键突变的假设数量以及干细胞和过渡细胞突变率。然而，在大多数情况下，癌症由诱变剂诱导的条件概率范围在7- 96%之间。与背景率相比，与诱变剂暴露相关的相对风险也是稳定的，范围为1.0-16.0。很少有癌症（通常<0.5%）是由干细胞中发生的突变引起的，而不是干细胞和转运细胞的组合。然而，对于具有2或3个关键突变的癌症，相当大比例的癌症，在某些情况下100%，具有至少一个源自突变干细胞的突变。如果允许部分转化的干细胞和转运细胞群体中增殖和分化的竞争过程，则相对风险几乎没有差异，如果假设转运细胞需要额外的突变来赋予干细胞所需数量的恶性肿瘤，则也没有任何差异。癌症被诱变剂诱导的概率在癌症部位与相关组织中干细胞分裂的估计累积数量相关（p<0.05），尽管在某些情况下，发现对去除高杠杆离群值具有敏感性，并且在某些情况下，概率仅存在适度变化，但这些问题不会影响发现的有效性。终生癌症部位特定辐射风险与诱变剂诱发癌症的概率之间没有显著相关性（p>0.3）。这些结果不依赖于假设的导致癌症的突变临界数量，也不依赖于假设的诱变剂相关突变率（在普遍接受的检测范围内）。然而，吸烟相关死亡率差异（当前吸烟者与既往吸烟者）与诱变剂诱发癌症的概率之间存在临界显著负相关（p = 0.08）。这仅适用于导致癌症的突变临界数k值为3或4的情况，而不适用于更小的值（1或2），但并不强烈依赖于假定的诱变剂相关突变率。癌症被认为是由细胞中的一系列突变引起的。由于突变是在细胞分裂后表达的，因此更新更快的组织可能会因为分裂次数更多而面临更高的风险。凯恩斯认为，组织可以通过将分裂的细胞群划分为不频繁分裂的干细胞和频繁分裂的子运输细胞的谱系来降低癌症风险。我们已经开发了三种最近的癌症模型的概括，这些模型解释了干细胞和转运细胞的联合维持和更新，特别关注评估与辐射或吸烟相关的癌症的机会。所有这三个模型都表明癌症风险的巨大变化，跨越二十多个数量级。然而，我们表明，如果癌症发生的机会，它是由一个显性诱变暴露是可变的，在一个数量级。很少有癌症是由单独发生在干细胞中的突变引起的，而不是干细胞和转运细胞的组合。然而，对于由2-3个突变引起的癌症，许多具有至少一个源自突变干细胞的突变。我们证实了突变剂诱发癌症的可能性与相关组织中干细胞分裂的累积数量相关的报道。
There is compelling biological data to suggest that cancer arises from a series of mutations in single target cells, resulting in defects in cell renewal and differentiation processes which lead to malignancy. Because much mutagenic damage is expressed following cell division, more-rapidly renewing tissues could be at higher risk because of the larger number of cell replications. Cairns suggested that renewing tissues may reduce cancer risk by partitioning the dividing cell populations into lineages comprising infrequently-dividing long-lived stem cells and frequently-dividing short-lived daughter transit cells. We develop generalizations of three recent cancer-induction models that account for the joint maintenance and renewal of stem and transit cells, also competing processes of partially transformed cell proliferation and differentiation/apoptosis. We are particularly interested in using these models to separately assess the probabilities of mutation and development of cancer associated with “spontaneous” processes and with those linked to a specific environmental mutagen, specifically ionizing radiation or cigarette smoking. All three models demonstrate substantial variation in cancer risks, by at least 20 orders of magnitude, depending on the assumed number of critical mutations required for cancer, and the stem-cell and transition-cell mutation rates. However, in most cases the conditional probabilities of cancer being mutagen-induced range between 7–96%. The relative risks associated with mutagen exposure compared to background rates are also stable, ranging from 1.0–16.0. Very few cancers, generally <0.5%, arise from mutations occurring solely in stem cells rather than in a combination of stem and transit cells. However, for cancers with 2 or 3 critical mutations, a substantial proportion of cancers, in some cases 100%, have at least one mutation derived from a mutated stem cell. Little difference is made to relative risks if competing processes of proliferation and differentiation in the partially transformed stem and transit cell population are allowed for, nor is any difference made if one assumes that transit cells require an extra mutation to confer malignancy from the number required by stem cells. The probability of a cancer being mutagen-induced correlates across cancer sites with the estimated cumulative number of stem cell divisions in the associated tissue (p<0.05), although in some cases there is sensitivity of findings to removal of high-leverage outliers and in some cases only modest variation in probability, but these issues do not affect the validity of the findings. There are no significant correlations (p>0.3) between lifetime cancer-site specific radiation risk and the probability of that cancer being mutagen-induced. These results do not depend on the assumed critical number of mutations leading to cancer, or on the assumed mutagen-associated mutation rate, within the generally-accepted ranges tested. However, there are borderline significant negative correlations (p = 0.08) between the smoking-associated mortality rate difference (current vs former smokers) and the probability of cancer being mutagen-induced. This is only the case where values of the critical number of mutations leading to cancer, k, is 3 or 4 and not for smaller values (1 or 2), but does not strongly depend on the assumed mutagen-associated mutation rate. Cancer is thought to arise from a series of mutations in cells. Because mutations are expressed following cell division, more-rapidly renewing tissues could be at higher risk because of the larger number of divisions. Cairns suggested that tissues may reduce cancer risk by partitioning the dividing cell populations into lineages of infrequently-dividing stem cells and frequently-dividing daughter transit cells. We have developed generalizations of three recent cancer models that account for the joint maintenance and renewal of stem and transit cells, with particular focus on assessing the chance of cancer associated with radiation or smoking. All three models demonstrate substantial variation in cancer risks, spanning over twenty orders of magnitude. However, we show that if cancer occurs the chance that it is caused by a dominant mutagenic exposure is less variable, within an order of magnitude. Few cancers arise from mutations occurring solely in stem cells rather than in a combination of stem and transit cells. However, for cancers arising from 2–3 mutations, many have at least one mutation derived from a mutated stem cell. We confirm reports that the probability of a cancer being mutagen-induced is associated with the cumulative number of stem cell divisions in the relevant tissue.