Krtolica A, Campisi J
Lawrence Berkeley National Laboratory, Life Sciences Division, Mailstop 84-171, 1 Cyclotron Road, Berkeley, CA 94720, USA.
Adv Gerontol. 2003;11:109-16.
Cancer incidence rises exponentially with age in humans and many other mammalian species. At least two critical changes are essential in order for cancer to develop: an accumulation of oncogenic mutations and a permissive tissue environment in which mutant cells can survive, proliferate, and express their neoplastic phenotype. Increasing evidence suggests that the rise in cancer with age results from a synergy between the accumulation of mutations and age-related, pro-oncogenic changes in the tissue milieu. Most age-related cancers derive from epithelial cells. Epithelial tissues are supported by a stroma, which is composed of extracellular matrix and several cell types. The stroma is essential for the function of the epithelium, and is maintained, remodeled and repaired by fibroblasts. One age-related change that occurs in epithelial tissues is the accumulation of senescent cells. Cellular senescence is a potent tumor suppressive mechanism that irreversibly arrests proliferation in response to damage or stimuli that put cells at risk for neoplastic transformation. Senescent cells, particularly senescent stromal fibroblasts, secrete factors that can disrupt tissue architecture and/or stimulate neighboring cells to proliferate. We suggest that senescent cells can create a tissue environment that synergizes with oncogenic mutations to promote the progression of age-related cancers. Recent evidence lends support to this idea, and suggests that cellular senescence may be an example of evolutionary antagonistic pleiotropy.
在人类和许多其他哺乳动物物种中，癌症发病率随年龄呈指数增长。癌症发生至少需要两个关键变化：致癌突变的积累以及突变细胞能够存活、增殖并表达其肿瘤表型的宽松组织环境。越来越多的证据表明，随着年龄增长癌症发病率上升是由于突变积累与组织微环境中与年龄相关的促癌变化之间的协同作用所致。大多数与年龄相关的癌症起源于上皮细胞。上皮组织由基质支撑，基质由细胞外基质和几种细胞类型组成。基质对于上皮功能至关重要，由成纤维细胞维持、重塑和修复。上皮组织中发生的与年龄相关的一种变化是衰老细胞的积累。细胞衰老一种强大的肿瘤抑制机制，它会响应使细胞有发生肿瘤转化风险的损伤或刺激而不可逆地阻止细胞增殖。衰老细胞，尤其是衰老的基质成纤维细胞，会分泌能够破坏组织结构和/或刺激邻近细胞增殖的因子。我们认为衰老细胞可以创造一种与致癌突变协同作用以促进与年龄相关癌症进展的组织环境。最近的证据支持了这一观点，并表明细胞衰老可能是进化拮抗多效性的一个例子。
