The origins of colorectal cancer (CRC) have long been a subject of intense debate. Early observations noted cancer formation in the human gut slightly above the base of crypts, the structural and functional units of the regenerative compartment of the intestinal epithelium. This suggested that the cells of origin for CRC reside close to the crypt-villus junction, where more differentiated cells are located. However, the specific induction of early cancer-initiating mutations within differentiated cells failed to initiate cancer. The subsequent identification of long-lived Lgr5+ intestinal stem cells and investigations into their role in cancer development further shifted the earlier views, leading to the widely accepted theory that CRC arises from stem cells and progenitors located at the base of crypts. A recent study published in Nature Genetics by Mathijs P. Verhagen and colleagues challenges this paradigm, providing compelling evidence that differentiated non-stem cell lineages, particularly Paneth cells, can serve as a source of intestinal tumorigenesis, especially in the context of inflammation and the consumption of a Western-style diet. This work significantly advances our understanding of the CRC initiation process and provides a new paradigm that may explain the increasingly higher incidence of CRC in younger people.

中文翻译：

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自下而上或自上而下：炎症重编程潘氏细胞以发展为肠癌


长期以来，结直肠癌 （CRC） 的起源一直是激烈争论的话题。早期观察注意到癌症在人体肠道中形成，略高于隐窝基部，隐窝是肠上皮再生隔室的结构和功能单位。这表明 CRC 的起源细胞位于隐窝-绒毛连接附近，那里有更多分化的细胞。然而，分化细胞内早期癌症起始突变的特异性诱导未能引发癌症。随后对长寿 Lgr5+ 肠道干细胞的鉴定和对其在癌症发展中作用的研究进一步改变了早期的观点，导致了被广泛接受的理论，即 CRC 起源于位于隐窝底部的干细胞和祖细胞。Mathijs P. Verhagen 及其同事最近发表在《自然遗传学》上的一项研究挑战了这种范式，提供了令人信服的证据，证明分化的非干细胞谱系，尤其是潘氏细胞，可以作为肠道肿瘤发生的来源，尤其是在炎症和西式饮食的情况下。这项工作显着促进了我们对 CRC 起始过程的理解，并提供了一种新的范式，可以解释年轻人 CRC 发病率越来越高。