Millán Magdalena, Parietti Felipe, Lamela Florencia, De Rossi María Cecilia, Benítez Belén, Levi Valeria, Domingues Manoela, Bologna-Molina Ronell, Arocena Miguel, Hochmann Jimena
Departamento de Biología Odontológica, Facultad de Odontología, Universidad de La República, General Las Heras 1925, Montevideo, Uruguay.
Departamento de Diagnóstico en Patología y Medicina Oral, Facultad de Odontología, Universidad de La República, General Las Heras 1925, Montevideo, Uruguay.
Histochem Cell Biol. 2025 Jan 3;163(1):23. doi: 10.1007/s00418-024-02350-5.
The tumor microenvironment is an altered milieu that imposes multiple selective pressures leading to the survival and dissemination of aggressive and fit tumor cell subpopulations. How pre-tumoral and tumoral cells respond to changes in their microenvironment will determine the subsequent evolution of the tumor. In this study, we have subjected pre-tumoral and tumoral cells to coverslip-induced hypoxia, which recapitulates the intracellular hypoxia and extracellular acidification characteristic of the early tumor microenvironment, and we have used a combination of quantitative phase microscopy and epifluorescence to analyze diverse cellular responses to this altered environment. In normoxia, tumor cells showed differences in nuclear organization, as evidenced by decreased numbers of HP1 foci, and in hypoxia major changes in nuclear architecture were observed, with tumor cells significantly increasing the number of high dry mass density foci in the nucleus compared to pre-tumoral and non-tumoral cells. Conversely, compared to pre-tumoral and normal cells, mitochondrial ATP levels decayed markedly in tumor cells in hypoxia, whereas the activation of executioner caspases increased only in tumor cells in this condition. Therefore, in terms of cellular organization, metabolic changes and activation of cell death processes, tumor cells showed more dramatic responses to an altered microenvironment than their pre-tumoral and normal counterparts, responses which in turn could play fundamental roles in shaping future tumor development.
肿瘤微环境是一种改变了的环境，它施加多种选择性压力，导致侵袭性且适应性强的肿瘤细胞亚群存活和扩散。肿瘤前细胞和肿瘤细胞如何应对其微环境的变化将决定肿瘤随后的演变。在本研究中，我们使肿瘤前细胞和肿瘤细胞经历盖玻片诱导的缺氧，这种缺氧模拟了早期肿瘤微环境的细胞内缺氧和细胞外酸化特征，并且我们使用定量相显微镜和落射荧光的组合来分析对这种改变的环境的多种细胞反应。在常氧条件下，肿瘤细胞在核组织方面表现出差异，如HP1灶数量减少所证明，而在缺氧条件下观察到核结构发生重大变化，与肿瘤前细胞和非肿瘤细胞相比，肿瘤细胞细胞核中高干质量密度灶的数量显著增加。相反，与肿瘤前细胞和正常细胞相比，缺氧条件下肿瘤细胞中的线粒体ATP水平明显下降，而在这种情况下，仅肿瘤细胞中的执行半胱天冬酶的激活增加。因此，在细胞组织、代谢变化和细胞死亡过程的激活方面，肿瘤细胞对改变的微环境的反应比其肿瘤前和正常对应细胞更显著，这些反应反过来可能在塑造未来肿瘤发展中发挥重要作用。
