Why malignant selfish cell lines, i.e. cancer, emerge in multicellular organisms, remains a contentious and unresolved question. The theory of carcinogenesis as the result of a multi‐stage Darwinian somatic selection process, postulated in the 1950s,^{[1, 2]} is now broadly accepted. Theoretical and empirical approaches have advanced since, and now incorporate the tissue environment of cancer cells, i.e. microenvironment, as a key player of cancer progression and evolution. Previous approaches proposed that “aging‐dependent somatic selection and life history‐dependent evolution of species‐specific tumour suppressor mechanisms” (quoted from ^[3]), need to be incorporated when attempting to understand cancer incidence across tissues and species.^{[3, 4]} Changes in the tissue environment as a consequence of aging have been proposed to present as an adaptive landscape for cancer‐causing mutations (that were maladaptive for the cancer cell at a younger age) to emerge, and no longer be eliminated.^{[3, 4]}

In this issue, Castillo et al.^[5] go beyond the concept of the aging tissue environment selecting new oncogenic phenotypes from random mutations, and propose a more systematic approach. They incorporate the Atavistic phenotype hypothesis (i.e. reactivation of ancestral genetic/phenotypic traits^[6]) into their approach, and postulate that malignancies emerge due to aging‐related breakdown of homeostatic regulations that facilitated and maintained cooperative strategies in a given tissue at a younger age. Aging changes the tissue microenvironment and thus compromises the integrity of the information on which a cell based its cooperative strategies in the multicellular cooperative context. Erosion of the message to cooperate triggers the transition between the functionally‐coupled collective (metazoan) and the non‐condensed cellular collectives (pre‐metazoan or pseudo‐multicellular state) and the re‐activation of the pre‐metazoan strategy (selfish proliferation), resulting in oncogenesis.

The authors apply the enactive hypothesis of Francisco Varela^[7] to argue that cancer emerges as a result of mutual co‐determination between the cell and its environment, the underlying mechanisms being natural selection, niche construction, and self‐organisation. While transitioning from a metazoan to a pre‐metazoan strategy in the aging tissue environment, the cells also modify their immediate external environment, and the level of selection shifts from the persistence of the collective to one where differential proliferation of the individual cell has higher fitness value.

While the authors recognise the necessity for over‐proliferation of a single cell for initiating cancer cell population establishment, they consider cancer cells and their microenvironment to be evolved cellular ecosystems. They postulate that it is cooperation that keeps the tissue together, and that when this is eroded, the cancer phenotype emerges.

The approach by Castillo et al.^[5] is novel and thought‐provoking, and should be considered when integrating epidemiology data into an evolutionary theory of carcinogenesis to produce an integrative, transdisciplinary understanding of cancer risk, and to develop more effective treatment strategies.

为什么恶性的自私细胞系（例如癌症）出现在多细胞生物体中，仍然是一个有争议且尚未解决的问题。1950年代^{[ 1，2 ]}提出的多阶段达尔文式体细胞选择过程致癌理论已被广泛接受。此后，理论和经验方法得到了发展，现在将癌细胞的组织环境（即微环境）纳入了癌症发展和演变的主要参与者。先前的方法提出“物种特异性肿瘤抑制机制的“依赖年龄的体细胞选择和依赖生活史的进化”（引自^{[ 3 ]}），在尝试了解跨组织和物种的癌症发病率时需要将其纳入。^{[ 3，4 ]}已经提出，由于衰老而导致的组织环境变化将作为适应性景观呈现出来，以引起癌症突变（在年轻时就适应不良的癌细胞），并且不再消除。 。^{[ 3，4 ]}

在这个问题上，卡斯蒂略等。^{[ 5 ]}超越了衰老组织环境的概念，从随机突变中选择新的致癌表型，并提出了一种更系统的方法。他们纳入了Atavistic表型假说（即重新激活祖先的遗传/表型特征^{[ 6 ]}）纳入其研究方法，并假设由于与衰老相关的体内稳态调节的破坏而出现了恶性肿瘤，这些稳态调节促进并维持了年轻组织中特定组织的合作策略。衰老改变了组织的微环境，因此损害了信息的完整性，在多细胞协作环境中，细胞基于其信息进行协作。协作信息的侵蚀触发了功能耦合的集体（metazoan）和非凝聚的细胞集体（metazoan或伪多细胞状态）之间的过渡，并重新激活了metazoan的策略（自私的增殖）。 ，导致肿瘤发生。

作者运用弗朗西斯科·瓦雷拉^（ Francisco Varela）的活跃假设^{[ 7 ]}来论证，癌症是细胞与环境之间共同决定的结果，其潜在机制是自然选择，利基构建和自我组织。在衰老的组织环境中从后生动物过渡到前偶氮动物的过程中，细胞还改变了其直接的外部环境，选择水平从集合体的持久性转变为单个细胞的差异增殖具有更高适应性的细胞值。

尽管作者认识到单个细胞过度增殖对于启动癌细胞群建立的必要性，但他们认为癌细胞及其微环境是进化的细胞生态系统。他们假定是合作使组织保持在一起，并且当这种组织被侵蚀时，就会出现癌症表型。

卡斯蒂略等人的方法。^{[ 5 ]}是新颖且发人深省的，在将流行病学数据整合到致癌作用的进化理论中以产生对癌症风险的综合，跨学科的理解并制定更有效的治疗策略时，应考虑^{[ 5 ]}。