INSERM U1081, IRCAN, NICE, France.
Subcell Biochem. 2022;98:189-204. doi: 10.1007/978-3-030-94004-1_10.
KRAS is the most frequently mutated oncogene in cancer and despite intensive studies, attempts to develop effective therapies targeting KRAS or its downstream signaling have failed mostly due to the complexity of KRAS activation and function in cancer initiation and progression. Over the years, KRAS has been involved in several biological processes including cell survival, proliferation, and metabolism by promoting not only a favorable tumor environment but also a cell-microenvironment dialog to allow cancer cells to adapt to tumor microenvironment scarcity. One of the mechanisms involved in this adaption is KRAS-mediated macropinocytosis. Macropinocytosis is an evolutionarily conserved, large-scale, and nonselective form of endocytosis involving actin-driven cell membrane remodeling to engulf large amounts of extracellular fluids and proteins from the local environment. While macropinocytosis process has been known for decades, recent gain interest due to its regulation of KRAS-driven tumor growth in adverse microenvironments. By promoting extracellular protein and other macromolecules internalization, macropinocytosis provides a survival mechanism under nutrient scarce conditions and the potential for unrestricted tumor growth. Thus, a better understanding of macropinocytotic process is needed to develop alternative therapeutic strategies.
KRAS 是癌症中最常发生突变的致癌基因，尽管进行了深入的研究，但由于 KRAS 在癌症发生和进展中的激活和功能的复杂性，靶向 KRAS 或其下游信号通路的有效治疗方法的尝试大多失败。多年来，KRAS 通过促进不仅有利于肿瘤环境，而且还促进细胞-微环境对话，使癌细胞能够适应肿瘤微环境的缺乏，从而参与了包括细胞存活、增殖和代谢在内的几个生物学过程。这种适应的机制之一是 KRAS 介导的巨胞饮作用。巨胞饮作用是一种进化上保守的、大规模的、非选择性的内吞作用形式，涉及肌动蛋白驱动的细胞膜重塑，以吞噬大量来自局部环境的细胞外液体和蛋白质。虽然巨胞饮作用过程已经存在了几十年，但由于其调节 KRAS 驱动的肿瘤在不利微环境中的生长，最近引起了人们的兴趣。通过促进细胞外蛋白质和其他大分子的内化，巨胞饮作用提供了在营养匮乏条件下的生存机制，并为无限制的肿瘤生长提供了潜力。因此，需要更好地了解巨胞饮作用过程，以开发替代治疗策略。
