Fallopian tube secreted protein affects ovarian metabolites in high grade serous ovarian cancer.
Fallopian tube secreted protein affects ovarian metabolites in high grade serous ovarian cancer.
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DOI：
10.3389/fcell.2022.1042734
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
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高级别浆液性卵巢癌（HGSOC）是最致命的卵巢癌组织类型，常发生于输卵管上皮细胞（FTE）。一旦转化，致瘤性FTE通常特异性地迁移到卵巢，完成关键的原发性转移步骤，并允许形成卵巢肿瘤，HGSOC最初被命名为卵巢肿瘤。由于只有靠近卵巢的输卵管远端才发生浆液性输卵管上皮内癌等前驱病变，这表明卵巢的转化和原发性转移过程受到局部微环境的影响。我们推测，化学线索，包括小分子和蛋白质，可能有助于刺激肿瘤FTE迁移到卵巢。然而，这一过程的具体介质仍然知之甚少，尽管最近在肿瘤微环境的兴趣增长。我们之前的工作利用成像质谱（IMS）来识别致瘤FTE细胞与卵巢外植体共培养物中卵巢释放的去甲肾上腺素（NE）。我们预测，致瘤FTE细胞分泌的生物分子，不产生或产生低表达的非致瘤细胞，刺激卵巢释放NE。因此，我们利用IMS质量引导的生物测定，使用NE释放作为我们的生物标志物，和自下而上的蛋白质组学来证明分泌蛋白，β-淀粉样蛋白，是由致瘤性FTE产生的因子，负责增强卵巢NE的释放和影响HGSOC的原发性转移。这一发现突出了输卵管和卵巢微环境中不同类型生物分子之间的双向相互作用，以及它们在原发性转移和疾病进展中的联合作用。
High grade serous ovarian cancer (HGSOC), the most lethal histotype of ovarian cancer, frequently arises from fallopian tube epithelial cells (FTE). Once transformed, tumorigenic FTE often migrate specifically to the ovary, completing the crucial primary metastatic step and allowing the formation of the ovarian tumors after which HGSOC was originally named. As only the fimbriated distal ends of the fallopian tube that reside in close proximity to the ovary develop precursor lesions such as serous tubal intraepithelial carcinomas, this suggests that the process of transformation and primary metastasis to the ovary is impacted by the local microenvironment. We hypothesize that chemical cues, including small molecules and proteins, may help stimulate the migration of tumorigenic FTE to the ovary. However, the specific mediators of this process are still poorly understood, despite a recent growth in interest in the tumor microenvironment. Our previous work utilized imaging mass spectrometry (IMS) to identify the release of norepinephrine (NE) from the ovary in co-cultures of tumorigenic FTE cells with an ovarian explant. We predicted that tumorigenic FTE cells secreted a biomolecule, not produced or produced with low expression by non-tumorigenic cells, that stimulated the ovary to release NE. As such, we utilized an IMS mass-guided bioassay, using NE release as our biological marker, and bottom-up proteomics to demonstrate that a secreted protein, SPARC, is a factor produced by tumorigenic FTE responsible for enhancing release of ovarian NE and influencing primary metastasis of HGSOC. This discovery highlights the bidirectional interplay between different types of biomolecules in the fallopian tube and ovarian microenvironment and their combined roles in primary metastasis and disease progression.
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