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对于生物，物竞天择、适者生存、弱肉强食、优胜劣汰是亘古不变的自然法则。对于人类，适应性（又称获得性、特异性、后天性）免疫系统利用细胞之间的信息交换，对外来细胞或受损细胞进行检测并清除；不过，并非必须适应性免疫系统才能清除不需要的细胞。例如，科学家发现果蝇细胞选择“适合度（又称适应值，是指在某种环境条件下，某一已知基因型的个体与其他基因型个体相比，能够生存并保留后代、将其基因传递到其后代基因库的相对能力，是衡量某一基因型个体生存和增殖机会、后代衍续能力的常用指标，适合度越大，对环境的适应能力越强，生存和增殖机会越高）指纹”竞争机制，可以延缓健康细胞老化、防止发育畸形、清除增殖缓慢细胞、通过再生对陈旧组织进行更新。适合度指纹从分子水平而言，包括不同结构的细胞膜花样蛋白。适合度降低的花样蛋白，由于表达于标记为可被清除的细胞膜表面，故被称为花样蛋白失败者。不过，细胞膜存在不同结构的花样蛋白失败者未必被清除，如果邻近细胞的花样蛋白失败者水平相似，那么自己不会被清除。由于在发育和老化过程中，如果已经受损但是仍然生存的细胞不断增多，可以引起器官功能障碍和疾病，故人类可以获益于识别不适应细胞的能力。不过，对于果蝇，该机制被癌前细胞利用而获得竞争生长优势。这对人类而言并不可取，因为该机制可能提高肿瘤的恶性程度。目前尚不清楚人类是否存在相似的细胞适合度比较机制。 2019年7月24日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表葡萄牙尚帕利莫研究中心、美国阿肯色医科大学、圣路易斯华盛顿大学、印第安纳大学、克瑞顿大学、达特茅斯学院、日本神奈川麻布大学、北海道大学、瑞士苏黎世大学的研究报告，发现不同结构的人类花样蛋白可以促进癌细胞竞争生长。 该研究利用人类乳腺癌细胞和乳腺组织，发现两种不同结构的人类花样蛋白hFWE1、hFWE3表现为花样蛋白失败者，而其他两种不同结构的人类花样蛋白hFWE2、hFWE4表现为花样蛋白获胜者。表达花样蛋白获胜者的细胞，与表达花样蛋白失败者的细胞相比，具有生存竞争优势。不过，如果邻近正常细胞表达花样蛋白失败者的水平相似，那么表达花样蛋白失败者的癌细胞不会被清除，故这些蛋白质发挥了“适合度指纹”的作用。此外，人类癌细胞的花样蛋白获胜者表达增加，并可增殖于存在花样蛋白失败者表达的细胞基质，从而赋予癌细胞竞争生长优势。抑制花样蛋白表达，可以减少肿瘤生长和转移，并且诱发肿瘤对化疗的敏感性。 因此，该研究结果表明，古老的细胞识别和选择机制也活跃于人类体内，并且可以影响肿瘤生长，花样蛋白有望成为乳腺癌的靶向治疗目标。 对此，日本北海道大学遗传基因病控制研究所藤田恭之教授发表同期报道：花样蛋白可以支配人类癌细胞与正常细胞竞争。 Nature. 2019 Jul 24. [Epub ahead of print] Flower isoforms promote competitive growth in cancer. 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. Champalimaud Centre for the Unknown, Lisbon, Portugal; University of Arkansas for Medical Sciences, Little Rock, AR, USA; Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO, USA; Azabu University, Kanagawa, Japan; Indiana University School of Medicine, Indianapolis, IN, USA; Creighton University, Omaha, NE, USA; University Hospital and University of Zurich, Zurich, Switzerland; Hokkaido University Hospital, Sapporo, Japan; Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA. 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 cell's 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 Nature. 2019 Jul 24. [Epub ahead of print] Flower power as human cancer cells compete with normal cells. Yasuyuki Fujita. Hokkaido University, Hokkaido, Japan. Cells compete for survival during development. It emerges that mammalian cells on a path to form a tumour express specific versions of the protein Flower when they vie for survival with surrounding normal cells. DOI: 10.1038/d41586-019-02161-y
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