Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
Sci Rep. 2021 Nov 25;11(1):22925. doi: 10.1038/s41598-021-02400-1.
Ovarian cancer is the most lethal gynecological cancer, and it is frequently diagnosed at advanced stages, with recurrences after treatments. Treatment failure and resistance are due to hypoxia-inducible factors (HIFs) activated by cancer cells adapt to hypoxia. IGFBP3, which was previously identified as a growth/invasion/metastasis suppressor of ovarian cancer, plays a key role in inhibiting tumor angiogenesis. Although IGFBP3 can effectively downregulate tumor proliferation and vasculogenesis, its effects are only transient. Tumors enter a hypoxic state when they grow large and without blood vessels; then, the tumor cells activate HIFs to regulate cell metabolism, proliferation, and induce vasculogenesis to adapt to hypoxic stress. After IGFBP3 was transiently expressed in highly invasive ovarian cancer cell line and heterotransplant on mice, the xenograft tumors demonstrated a transient growth arrest with de-vascularization, causing tumor cell hypoxia. Tumor re-proliferation was associated with early HIF-1α and later HIF-2α activations. Both HIF-1α and HIF-2α were related to IGFBP3 expressions. In the down-expression of IGFBP3 in xenograft tumors and transfectants, HIF-2α was the major activated protein. This study suggests that HIF-2α presentation is crucial in the switching of epithelial ovarian cancer from dormancy to proliferation states. In highly invasive cells, the cancer hallmarks associated with aggressiveness could be activated to escape from the growth restriction state.
卵巢癌是最致命的妇科癌症，通常在晚期诊断，治疗后会复发。治疗失败和耐药性是由于癌细胞激活的缺氧诱导因子（HIFs）适应缺氧环境。IGFBP3 先前被鉴定为卵巢癌的生长/侵袭/转移抑制剂，在抑制肿瘤血管生成中起关键作用。尽管 IGFBP3 可以有效地下调肿瘤增殖和血管生成，但它的作用只是暂时的。当肿瘤生长到足够大且没有血管时，就会进入缺氧状态；然后，肿瘤细胞激活 HIFs 来调节细胞代谢、增殖，并诱导血管生成以适应缺氧应激。在高度侵袭性卵巢癌细胞系中短暂表达 IGFBP3 并在小鼠中异基因移植后，异种移植瘤表现出短暂的生长停滞和去血管化，导致肿瘤细胞缺氧。肿瘤的再增殖与早期 HIF-1α 和晚期 HIF-2α 的激活有关。HIF-1α 和 HIF-2α 均与 IGFBP3 的表达有关。在异种移植瘤和转染细胞中 IGFBP3 的低表达中，HIF-2α 是主要的激活蛋白。这项研究表明，HIF-2α 的表达在从休眠到增殖状态的上皮性卵巢癌转变中至关重要。在高度侵袭性的细胞中，与侵袭性相关的癌症特征可能被激活，以逃避生长限制状态。
