近日，来自葡萄牙的Eduardo Moreno和Rajan Gogna研究团队合作揭示了肿瘤组织中的一类竞争性生长模式。相关论文于2019年8月8日发表在《自然》上。

在人类中，适应性免疫系统利用细胞之间的信息交换来检测和清除外来或受损细胞; 然而，去除不需要的细胞并不总是需要适应性免疫系统。例如，果蝇中的细胞选择使用一个基于“健康指纹”的细胞选择机制，来实现其延缓衰老，防止发育畸形以及在再生过程中替换旧组织。在分子水平上，这些健身指纹由膜蛋白Flower的组合所组成。代表适应性降低的蛋白质被称为Flower-Lose，因为它们在标记为被清除的细胞中表达。然而，在细胞膜上Flower-Lose亚型的存在并不总是导致清除，因为如果相邻细胞具有近似水平的Lose蛋白，则细胞不会被杀死。人类可以从识别不合格细胞的能力中受益，因为在发育和衰老过程中受损但存活的细胞的积累会导致器官功能障碍与疾病。然而，在果蝇中，这种机制被癌前细胞利用以获得竞争性生长优势。这对人类来说是不想要的，因为它可能使肿瘤更具侵略性。目前尚不清楚人类是否存在类似的细胞适应性竞争机制。

研究人员发现了两种人类Flower蛋白亚型（hFWE1和hFWE3）是Flower-Lose蛋白，而另外两种亚型（hFWE2和hFWE4）是Flower-Win蛋白。后者比表达Lose亚型的细胞更具有竞争优势，但如果它们的邻近细胞表达相似水平的Lose亚型，则不会清除表达Lose的细胞。因此，这些蛋白可作为健康指纹。此外，人类癌细胞显示Win亚型表达的增加并且在表达Lose的基质存在下增殖，这赋予癌细胞竞争性生长优势。抑制Flower蛋白的表达可减少肿瘤生长和转移，并引起其对化疗的敏感性。这些研究结果表明，细胞识别和选择的古老机制在人类中起作用并影响致癌生长。

附：英文原文

Title: Flower isoforms promote competitive growth in cancer

Author: Esha Madan, Christopher J. Pelham, Masaki Nagane, Taylor M. Parker, Rita Canas-Marques, Kimberly Fazio, Kranti Shaik, Youzhong Yuan, Vanessa Henriques, Antonio Galzerano, Tadashi Yamashita, Miguel Alexandre Ferreira Pinto, Antonio M. Palma, Denise Camacho, Ana Vieira, David Soldini, Harikrishna Nakshatri, Steven R. Post, Christa Rhiner, Hiroko Yamashita, Davide Accardi, Laura A. Hansen, Carlos Carvalho, Antonio L. Beltran, Periannan Kuppusamy, Rajan Gogna, Eduardo Moreno

Issue&Volume:  Volume 572 Issue 7768

Abstract: In humans, the adaptive immune system uses the exchange of information between cells to detect and eliminate foreign or damaged cells; however, the removal of unwanted cells does not always require an adaptive immune system. For example, cell selection in Drosophila uses a cell selection mechanism based on fitness fingerprints, which allow it to delay ageing, prevent developmental malformations and replace old tissues during regeneration. At the molecular level, these fitness fingerprints consist of combinations of Flower membrane proteins. Proteins that indicate reduced fitness are called Flower-Lose, because they are expressed in cells marked to be eliminated. However, the presence of Flower-Lose isoforms at a cells membrane does not always lead to elimination, because if neighbouring cells have similar levels of Lose proteins, the cell will not be killed. Humans could benefit from the capability to recognize unfit cells, because accumulation of damaged but viable cells during development and ageing causes organ dysfunction and disease. However, in Drosophila this mechanism is hijacked by premalignant cells to gain a competitive growth advantage. This would be undesirable for humans because it might make tumours more aggressive. It is unknown whether a similar mechanism of cell-fitness comparison is present in humans. Here we show that two human Flower isoforms (hFWE1 and hFWE3) behave as Flower-Lose proteins, whereas the other two isoforms (hFWE2 and hFWE4) behave as Flower-Win proteins. The latter give cells a competitive advantage over cells expressing Lose isoforms, but Lose-expressing cells are not eliminated if their neighbours express similar levels of Lose isoforms; these proteins therefore act as fitness fingerprints. Moreover, human cancer cells show increased Win isoform expression and proliferate in the presence of Lose-expressing stroma, which confers a competitive growth advantage on the cancer cells. Inhibition of the expression of Flower proteins reduces tumour growth and metastasis, and induces sensitivity to chemotherapy. Our results show that ancient mechanisms of cell recognition and selection are active in humans and affect oncogenic growth.

DOI: 10.1038/s41586-019-1429-3

Source: https://www.nature.com/articles/s41586-019-1429-3