Krtolica Ana, Campisi Judith
Lawrence Berkeley National Laboratory, Life Sciences Division, Mailstop 84-171, 1 Cyclotron Road, Berkeley, CA 94720, USA.
Int J Biochem Cell Biol. 2002 Nov;34(11):1401-14. doi: 10.1016/s1357-2725(02)00053-5.
The incidence of cancer rises exponentially with age in humans and many other mammalian species. Malignant tumors are caused by an accumulation of oncogenic mutations. In addition, malignant tumorigenesis requires a permissive tissue environment in which mutant cells can survive, proliferate, and express their neoplastic phenotype. We propose that the age-related increase in cancer 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 the epithelial cells of renewable tissues. An important element of epithelial tissues is the stroma, the sub-epithelial layer composed of extracellular matrix and several cell types. The stroma is maintained, remodeled and repaired by resident fibroblasts, supports and instructs the epithelium, and is essential for epithelial function. One change that occurs in tissues during aging is the accumulation of epithelial cells and fibroblasts that have undergone cellular senescence. Cellular senescence irreversibly arrests proliferation in response to damage or stimuli that put cells at risk for neoplastic transformation. Senescent cells secrete factors that can disrupt tissue architecture and/or stimulate nearby cells to proliferate. We therefore speculate that their presence may create a pro-oncogenic tissue environment that synergizes with oncogenic mutations to drive the rise in cancer incidence with age. Recent evidence lends support to this idea, and suggests that senescent stromal fibroblasts may be particularly adept at creating a tissue environment that can promote the development of age-related epithelial cancers.
在人类和许多其他哺乳动物物种中，癌症的发病率随年龄呈指数增长。恶性肿瘤是由致癌突变的积累引起的。此外，恶性肿瘤发生需要一个允许突变细胞存活、增殖并表达其肿瘤表型的组织环境。我们提出，与年龄相关的癌症增加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可再生组织的上皮细胞。上皮组织的一个重要组成部分是基质，即由细胞外基质和几种细胞类型组成的上皮下层。基质由驻留的成纤维细胞维持、重塑和修复，支持并指导上皮细胞，对上皮功能至关重要。衰老过程中组织发生的一个变化是经历细胞衰老的上皮细胞和成纤维细胞的积累。细胞衰老会因损伤或使细胞有发生肿瘤转化风险的刺激而不可逆地阻止增殖。衰老细胞分泌的因子可破坏组织结构和/或刺激附近细胞增殖。因此，我们推测它们的存在可能会创造一个促癌的组织环境，与致癌突变协同作用，推动癌症发病率随年龄增长而上升。最近的证据支持了这一观点，并表明衰老的基质成纤维细胞可能特别擅长创造一种能够促进与年龄相关的上皮癌发展的组织环境。
