廖联明   编译

在第一个研究性激素对肠道干细胞影响的研究中，科学家们提出了新的见解，表明在结构和功能上与人体类固醇激素相似的类固醇性激素，如何彻底改变肠干细胞的行为方式，最终影响到肠道器官的整体结构和功能。作者发现，蜕皮激素，一种由果蝇产生的类固醇激素，它能刺激肠道干细胞的生长，使雌性果蝇的肠道变大，并诱导其他显著的变化。这项研究还提出了一种解释肠道干细胞在正常肠道功能中的性别差异性作用的机制。此外，这项还研究提出肠道激素可能加速肿瘤恶化的证据。犹他大学亨斯迈癌症研究所(HCI)和德国癌症研究中心(DKFZ)联合报道了这一发现，研究结果发表在《自然》杂志上。

 美国大学肿瘤科学教授Bruce Edgar博士和海德堡大学教授Aurelio Teleman共同领导了这项研究。他们想弄清楚问性激素是否影响肠干细胞的增殖能力和促进肠道生长。

 我们知道雄性和雌性果蝇的肠道有差异——例如，雌性果蝇的肠道比雄性果蝇大，而且雌性果蝇比雄性果蝇更容易患肠道肿瘤——但我们不知道其中的原因。

 这项研究为这些差异以及它们是如何产生的提供了重要的见解。

 Edgar和Teleman的研究团队发现，蜕皮激素是一种特殊的性激素，可以极大地改变器官中干细胞的生长特性，而这个器官并不直接参与生殖。他们发现，这些变化会影响整个器官的结构和功能。他们发现，给雄性苍蝇注射蜕皮激素会使它们原本分裂缓慢的干细胞分裂速度和雌性一样快，从而导致雄性果蝇的肠道生长。这表明，导致雄性和雌性果蝇干细胞分裂的限差异是荷尔蒙的循环水平。

 这一过程给雌性果蝇在其生命过程中带来了利与弊。最初，雌性体内更多的蜕皮激素有助于生殖的进化关键过程。它促进肠道增大，促进营养吸收，帮助雌性果蝇产卵。但在生命的后期，由卵巢产生的蜕皮激素最终会导致肠道功能紊乱，通过创造有利于肿瘤生长的环境，从而缩短雌性果蝇的寿命。虽然人类不产生蜕皮激素，但人类确有相关的类固醇激素，如雌激素、黄体酮和睾酮，它们的作用机制相似。

 这项研究提供了确凿的证据，证明性激素会改变肠道等非性器官的行为。这项研究的长期意义可能使探索治疗人类癌症的新途径。

 根据研究人员的说法，了解人类器官中是否存在类似的干细胞-激素关系还需要进一步的研究。他们计划在未来对此进行探索。除了性激素在肠道干细胞行为中扮演的关键角色之外，作者认为，这项针对果蝇的研究可能揭示了一种可能在人类生理和病理中发挥作用的新机制。从这项研究的中得到的见解增加了越来越多的研究内容，表明包括结肠癌和胃癌在内的非生殖器官癌症的发病率在男性和女性中是不同的。

Journal Reference:

Fitness trade-offs incurred by ovary-to-gut steroid signalling in Drosophila. Nature, 2020; DOI: 10.1038/s41586-020-2462-y

New clues about the critical role of sex hormones in stem cell control

In one of the first studies addressing the role of sex hormones' impact on stem cells in the gut, scientists outline new insights showing how a steroidal sex hormone, that is structurally and functionally similar to human steroid hormones, drastically alters the way intestinal stem cells behave, ultimately affecting the overarching structure and function of this critical organ. The authors found that ecdysone, a steroid hormone produced by fruit flies, stimulates intestinal stem cell growth and causes the gut of the female fruit fly to grow in size, and induces other critical changes. The study also provides a mechanism to account for sex-specific roles for intestinal stem cells in normal gut function. Moreover, the research presents evidence that gut hormones may accelerate tumor development. The findings, reported jointly by Huntsman Cancer Institute (HCI) at the University of Utah (U of U) and the German Cancer Research Center (DKFZ), are published in the journal Nature.

Bruce Edgar, PhD, a professor of oncological sciences at the U of U, together with Aurelio Teleman, PhD, professor at Heidelberg University jointly led the work. They asked whether sex hormones affect intestinal stem cells' ability to multiply and contribute to gut growth.

We knew that male and female fruit flies exhibited differences in their intestine -- for example, the female's intestine is larger than the male's, and females develop intestinal tumors much more readily than males -- but we didn't know why.

This study adds significant insights into these differences, and how they arise.

The Edgar and Teleman teams found that ecdysone, a sex-specific hormone, can drastically alter the growth properties of stem cells in an organ that, remarkably, is not directly involved in reproduction. They found that these changes affect the structure and function of the entire organ. They discovered that subjecting male flies to ecdysone caused their otherwise slow dividing stem cells to divide as fast as in females, leading to intestinal growth in males as well. This suggests that the limiting difference between the division of stem cells in male and female flies is the circulating levels of the hormone.

This process confers both advantages and disadvantages to the female fruit fly during the course of its life. Initially, more ecdysone in females helps with the evolutionarily critical processes of reproduction. It promotes gut enlargement, facilitating nutrient absorption, which helps the fly lay more eggs. But later in life, the ecdysone hormone, produced by the ovaries, eventually causes gut disfunction that can shorten the lifespan in female fruit flies by creating an environment that favors tumor growth. While humans don't produce ecdysone, they do have related steroid hormones such as estrogen, progesterone and testosterone, which have similar mechanisms of action.

The study provides conclusive evidence that sex hormones alter the behavior of non-sex organs like the intestine. The long-term implications of this research may include exploration of new paths to treating human cancers.

According to the researchers, understanding whether a similar stem cell-hormone relationship operates in human organs will require further studies. They plan to explore this in the future. In addition to the critical role played by sex hormones in intestinal stem cell behavior, the authors believe this study in Drosophila potentially unveils a new mechanism that may play out in human physiology and pathology. Insights from this study add to a growing body of work showing that the incidence cancers of non-reproductive organs, including colon and gastric cancers, are different in males and females.