Parkinson Eric Kenneth, James Emma L, Prime Stephen S
Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Gerontology. 2016;62(4):417-24. doi: 10.1159/000440954. Epub 2015 Dec 3.
Oral cancers are predominantly oral squamous cell carcinomas (OSCCs) derived from keratinocytes, and there is now very detailed knowledge of the genetics and molecular biology of the epithelial tumourigenic component of these cancers, including the identification of cancer stem or tumour-initiating cells. Several key genetic alterations have been identified including the near ubiquitous loss of the CDKN2A/p16INK4A and p53 pathways and telomerase activation, together with frequent inactivation of the NOTCH1 canonical pathway either by somatic genetic alterations or by the presence of human papilloma virus. There is also evidence that OSCCs arise from a 'field' of altered cells and that malignant conversion takes place pre-dominantly at the microscopic level. However, in the last decade, it has been realised that tumour development and progression are influenced by the cells of the microenvironment with cross-talk between the epithelial (tumour) and mesenchymal components. OSCCs, especially those that have bypassed cellular senescence, produce an array of proteins and metabolites that induce cellular senescence in the normal surrounding cells; indeed, senescence is a common property of cancer-associated fibroblasts (CAFs). Cellular senescence is defined as an irreversible cell cycle arrest and is associated with the release of molecules known as the senescence-associated secretory phenotype that can selectively promote the growth of pre-neoplastic keratinocytes (osteopontin) and cancer invasion (transforming growth factor β, matrix metalloproteinases, interleukin 6 and lactate). In addition, both old and new work has shown that keratinocytes harbouring NOTCH loss-of-function mutations that lead to defective keratinocyte differentiation and loss of squamous epithelial barrier function may act as a tumour-promoting stimulus for initiated cells harbouring RAS pathway mutations by activating a wound response in the tumour mesenchyme. Thus, not all keratinocytes in the tumour tissue may be tumourigenic and may instead act as promoters of tumour growth and progression analogous to the much-studied CAFs which co-evolve with the genetically altered tumourigenic cells. This new data is discussed in relation to attempts to develop novel non-invasive diagnostics and therapeutics for oral cancer.
口腔癌主要是源自角质形成细胞的口腔鳞状细胞癌（OSCC），目前对于这些癌症上皮致瘤成分的遗传学和分子生物学已有非常详尽的了解，包括癌症干细胞或肿瘤起始细胞的鉴定。已鉴定出几种关键的基因改变，包括CDKN2A/p16INK4A和p53通路几乎普遍缺失以及端粒酶激活，同时NOTCH1经典通路频繁因体细胞基因改变或人乳头瘤病毒的存在而失活。也有证据表明，OSCC源自一个改变细胞的“区域”，恶性转化主要发生在微观层面。然而，在过去十年中，人们已经认识到肿瘤的发生和进展受到微环境细胞的影响，上皮（肿瘤）和间充质成分之间存在相互作用。OSCC，尤其是那些绕过细胞衰老的OSCC，会产生一系列蛋白质和代谢产物，这些产物会在周围正常细胞中诱导细胞衰老；事实上，衰老是癌症相关成纤维细胞（CAF）的一个共同特性。细胞衰老被定义为不可逆的细胞周期停滞，并与称为衰老相关分泌表型的分子释放有关，这些分子可选择性促进肿瘤前角质形成细胞（骨桥蛋白）的生长和癌症侵袭（转化生长因子β、基质金属蛋白酶、白细胞介素6和乳酸）。此外，新的和旧的研究都表明，携带导致角质形成细胞分化缺陷和鳞状上皮屏障功能丧失的NOTCH功能丧失突变型角质形成细胞，可能通过激活肿瘤间充质中的伤口反应，对携带RAS通路突变的起始细胞起到促肿瘤刺激作用。因此，肿瘤组织中的并非所有角质形成细胞都具有致瘤性，相反，它们可能起到促进肿瘤生长和进展的作用，类似于与基因改变的致瘤细胞共同进化的、已被深入研究的CAF。本文结合开发口腔癌新型非侵入性诊断和治疗方法的尝试对这些新数据进行了讨论。
