Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Am J Obstet Gynecol. 2013 Dec;209(6):576.e1-576.e16. doi: 10.1016/j.ajog.2013.08.004. Epub 2013 Aug 9.
The objective of the study was to evaluate the biological validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival.
Using genome-wide expression profiling and deoxyribonucleic acid sequencing, we compared pelvic and matched extrapelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage vs metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in 9 independent clinicogenomic datasets from 1691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of 1 pathway (transforming growth factor [TGF]-WNT) on in vitro OVCA cell migration were studied.
Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration.
Advanced-stage OVCA has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.
本研究旨在评估卵巢癌（OVCA）筛查和早期检测工作的生物学有效性，并阐明与人类癌症转移和患者生存相关的信号通路。
我们采用全基因组表达谱和脱氧核糖核酸测序技术，比较了 30 例晚期 OVCA 患者盆部和盆外转移灶中分子信号通路的表达情况，同时分析了 p53 基因突变情况。我们进一步在 389 例卵巢癌、前列腺癌和口腔癌患者的原发性或早期肿瘤与转移性或复发性肿瘤样本中评估了差异表达的通路。我们还在 1691 例卵巢癌、乳腺癌、结肠癌、脑癌和肺癌及白血病患者的 9 个独立临床基因组学数据集中评估了转移通路与生存的相关性。我们还研究了 1 条通路（转化生长因子[TGF]-WNT）对体外 OVCA 细胞迁移的抑制作用。
盆部和盆外 OVCA 转移灶表现出相似的信号通路表达模式，且具有相同的 p53 突变。然而，我们在盆部和盆外 OVCA 样本、原发性/早期肿瘤与转移性/晚期或复发性卵巢癌、口腔癌和前列腺癌之间，鉴定出 3 条差异表达的分子通路/细胞过程。此外，这些通路的表达与卵巢癌（P=0.006）、结肠癌（1 条通路，P=0.005）和白血病（P=0.05）患者的总生存相关。青蒿琥酯诱导的 TGF-WNT 通路抑制可削弱 OVCA 细胞迁移。
晚期 OVCA 起源于盆部的单一病灶。与盆外 OVCA 播散相关的分子通路也与其他人类癌症的转移和患者总体生存相关。这些通路可能是转移性疾病患者有吸引力的治疗靶点。
