Exposure of the extracellular matrix and colonization of the ovary in metastasis of fallopian-tube-derived cancer
Exposure of the extracellular matrix and colonization of the ovary in metastasis of fallopian-tube-derived cancer
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DOI：
10.1093/carcin/bgy170
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发表时间：
2019-01-01
期刊：
影响因子：
4.7
通讯作者：
Burdette, Joanna E.
中科院分区：
文献类型：
--
作者：
Dean, Matthew;Jin, Vivian;Burdette, Joanna E.
卵巢癌可以起源于输卵管。我们发现，卵巢定植，暴露的卵巢细胞外基质，将发生在排卵期间，和损失的PTEN在输卵管是重要的传播这种diseases.Abstract高级别浆液性卵巢癌（HGSOC）可以起源于输卵管上皮（FTE），但卵巢在这些肿瘤中的作用还不清楚。致瘤性小鼠输卵管上皮（莫伊）细胞同种异体移植在卵巢囊中导致侵袭性肿瘤扩散到整个腹膜，而腹腔内异种移植相同数量的细胞没有形成肿瘤，表明卵巢的定植可能在转移中发挥作用。物理撕裂卵巢表面模拟排卵期间卵巢破裂（与激素变化无关），导致与完整卵巢相比，更多的莫伊和HGSOC细胞粘附在卵巢上。与卵巢表面上皮细胞相比，更多的莫伊细胞粘附于三维（3D）胶原和原代卵巢基质细胞，表明FTE细胞粘附于排卵期间暴露的细胞外基质。然而，将细胞接种在3D胶原蛋白上会降低正常FTE的活力，但不会降低癌细胞的活力。p53突变（R273 H或R248 W）和Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）（G12 V）的激活不会增加莫伊细胞在3D胶原上的生存力。相比之下，磷酸酶和张力蛋白同源物（PTEN）的损失允许莫伊细胞在3D胶原蛋白上保持正常活力。PTEN的缺失激活了AKT和RAC 1/c-jun N-末端激酶信号传导，它们各自促进了在富含胶原的卵巢微环境中的活力、侵袭和附着的增加。这些结果表明，PTEN的丢失激活了多个途径，这些途径由于接近3D胶原蛋白而共同增强了卵巢的定殖，3D胶原蛋白是FTE衍生的HGSOC定殖中的关键器官。
Ovarian cancer can originate in the fallopian tube. We show that ovarian colonization, exposure of the ovarian extra-cellular matrix as would occur during ovulation, and loss of PTEN in the fallopian tube are important for spread of this disease.Abstract High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube epithelium (FTE), but the role of the ovary in these tumors is unclear. Tumorigenic murine oviductal epithelial (MOE) cells allografted in the ovarian bursa resulted in aggressive tumors that spread throughout the peritoneum whereas intraperitoneal xenografting the same number of cells did not form tumors, indicating that colonization of the ovary may play a role in metastasis. Physical tearing of the ovarian surface to mimic rupture of the ovary during ovulation (independent of hormonal changes) resulted in more MOE and HGSOC cells adhering to the ovary compared with intact ovaries. More MOE cells also adhered to three-dimensional (3D) collagen and primary ovarian stromal cells than to ovarian surface epithelia, indicating that FTE cells adhered to the extracellular matrix exposed during ovulation. However, plating cells on 3D collagen reduced the viability of normal FTE but not cancer cells. Mutation of p53 (R273H or R248W) and activation of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) (G12V) did not increase the viability of MOE cells on 3D collagen. In contrast, loss of phosphatase and tensin homolog (PTEN) allowed MOE cells to retain normal viability on 3D collagen. Loss of PTEN activated AKT and RAC1/c-jun N-terminal kinase signaling that each contributed to the increased viability, invasion and attachment in the collagen rich ovarian microenvironment. These results show that loss of PTEN activates multiple pathways that together enhance colonization of the ovary due to access to 3D collagen, which is a critical organ in the colonization of FTE-derived HGSOC.