生殖细胞发育潜能激活在畸胎瘤/癌起源中的作用

The similarities between germline / embryonic development and tumor formation has long been appreciated, include: immortalization (involved in transformation), invasion, induction of meiosis (leading to aneuploidy) and migration (contributes to metastasis), demethylation, downregulation of the major histocompatibility complex (immune evasion) and expression of chorionic gonadotropin. Base on the similarities, scientists speculated that tumors are in some way related to the formation of gametes and to fertilization. Someone attributed it to tumors arising from germ cells that fail to complete their embryonic migration to the gonads. But someone point out the germline/embryonic development features of tumors might attribute to somatic cells that have undergone a de-differentiation/gametogenic program activation. However, it is still not clear what kind of concept is true. Our previous studies showed that transformed mouse bone marrow-derived cells (BMDCs),transformed human hepatic cells and mouse fibrosarcoma cells (derived from normal subcutaneous areolar and adipose tissue) could generate germline-like cells in vitro and give rise to teratoma/teratocarcinomas in vivo. The results established a direct link between cells drived from saomatic tissues and teratoma/teratocarcinoma, which will benefit to further investigate why tumors possess strong germline/embryonic traits. It has been reported that somatic cells could re-obtain the features of germline/embryonic under special condition. Therefore, we plan to confirm whether carcinogenesis condition can trigger the germline potential of human BMDCs. That is, germline/ embryonic features of transformed hBMDCs should attribute to the reactiveation of germline potential not but germline cell residing in BMDCs. Activation of germline potential in somatic cells under carcinogenesis condition will provide evidences for the origin of tertoma/teratocarcinomas from somatic cells. Secondary, the positive results will provide evidences for the concept that de-differentiation/ gametogenic program activation appears in the process of carcinogenesis. Moreover, the results will be benefit to better understand why somatic cancer cells have strong features of germline/embryonic development and better understand the tumor biology.

肿瘤具有高度生殖细胞/胚胎发育轴特性，然而到底是由于"胚胎残余/异位生殖细胞"还是由于体细胞的"去分化/配子发育程序重新激活"导致了此现象？至今仍然未知。我们前期研究发现：癌变小鼠骨髓细胞、癌变人肝细胞株和小鼠纤维肉瘤细胞株均具有产生畸胎瘤/癌和生殖细胞样细胞的能力；将成体组织来源细胞和畸胎瘤/癌紧紧地联系到了一起。文献报道：在一定的条件下，体细胞具有向生殖细胞/胚胎细胞转化的潜能。因此在本课题中我们拟以人骨髓细胞为研究对象，证实癌变骨髓细胞产生畸胎瘤/癌和生殖细胞的能力是在癌变过程中获得的，而非其中本来就含有生殖细胞。即癌变条件具有激活体细胞向"生殖细胞转化"的能力。癌变因素可导致"体细胞的生殖细胞发育潜能激活"的证实；①将为畸胎瘤/癌可以起源于体细胞提供有力的实验证据；②将有利于解释"肿瘤为什么具有高度生殖细胞/胚胎发育轴特性？"③将为肿瘤的"去分化/配子形成理论"提供实验支持。

畸胎瘤/癌从何而来？是由于体细胞中存在着“异位生殖细胞/胚胎细胞呢？”还是由于癌变激活了体细胞的“生殖细胞/胚胎发育轴潜能”导致的呢？我们使用化学致癌剂3-甲基胆蒽（3-MCA）处理人骨髓细胞（human bone marrow-derived cells, hBMDCs）。在本课题中我们研究发现：化学致癌剂3-MCA能够激活人骨髓细胞的生殖细胞发育潜能，该细胞能够进一步分化产生更为成熟的生殖细胞样细胞及胚样衍生物；在体内能够产生含有成熟组织的畸胎瘤/癌样肿瘤。该实验结果表明：癌变骨髓细胞产生生殖细胞及畸胎瘤的能力是在癌变过程中获得的，化学致癌剂能够激活骨髓细胞的生殖细胞发育潜能。即：畸胎瘤/癌可以起源于成体组织来源细胞的“生殖细胞/胚胎发育轴潜能”的激活。. 随后，我们从敲入Oct4-GFP基因的小鼠中分离出骨髓细胞（Bone marrow-derived cells）为研究模型，以Oct4-GFP指示生殖细胞样细胞的出现；以进一步研究生殖细胞样细胞的出现和肿瘤恶性特征之间的关系。我们的实验结果显示：化学致癌剂3-MCA处理后，大多数分化细胞老化而上层细胞开始出现Oct4-GFP+细胞；Oct4-GFP+生殖细胞样细胞的出现早于明显的恶性转化特征的出现，如形态改变、接触抑制、停泊独立性、失去极性、快速生长、悬浮生长、肿瘤形成。Oct4-GFP+细胞具有分化产生体细胞样细胞、生殖细胞样细胞、胚样衍生物及在裸鼠体内形成肿瘤的能力。因此，我们的实验结果提示; 胚胎/生殖细胞样细胞的出现是在致癌剂诱导骨髓细胞具有成瘤性之前，因而胚胎/生殖细胞样细胞的出现可能在致癌性中具有关键性作用。.因此，我们的实验结果提示：① 畸胎瘤/癌可以起源于体细胞的生殖细胞发育潜能激活，与本课题的实验假说一致； ② “癌变因素诱导生殖细胞潜能的激活”可以解释"肿瘤为什么具有高度生殖细胞/胚胎发育轴特性？”，并为肿瘤的"去分化/配子形成理论"提供实验支持，进而为肿瘤的“胚胎/生殖细胞发育假说”提供有力的实验支持。③ 初步建立了肿瘤的高度胚胎/生殖细胞特性与其恶性特性间的紧密联系。.