Ovarian metastases exfoliate from the primary tumor and it is thought that aggregation supports their survival in the peritoneal cavity during dissemination but the underlying mechanisms are not clearly identified. We have previously shown that ovarian cancer cells acquire an increasingly glycolytic and metabolic flexible phenotype during progression. In the present study, we investigated how hypoxia, aggregation, and the incorporation of the obese stromal vascular fraction (SVF) affect cellular metabolism and the response to common anti-cancer and anti-diabetic drugs. Our results show a reduction of glucose uptake, lactate secretion, cellular respiration and ATP synthesis in response to hypoxia and aggregation, suggesting that the observed reduced proliferation of cells aggregated into spheroids is the result of a down-regulation of respiration. Recruitment of SVF to spheroids increased the spheroids invasive capacity but reduced respiration only in the most aggressive cells. Further, aggregation and hypoxia reduced the response to the metabolic drugs AICAR and metformin, and the chemotherapeutic agents cisplatin and paclitaxel. Our results suggest that the adaptation of cellular metabolism may contribute to enhanced survival under non-permissive conditions, and that these metabolic alterations may provide targets for future interventions that aim to enhance the survival of women with metastatic ovarian cancer.

卵巢转移从原发性肿瘤中剥落，据认为聚集在扩散过程中支持其在腹膜腔中的存活，但其潜在机制尚不清楚。先前我们已经表明，卵巢癌细胞在进展过程中获得了越来越多的糖酵解和代谢柔性表型。在本研究中，我们调查了缺氧，聚集和肥胖基质血管部分（SVF）的掺入如何影响细胞代谢以及对常见抗癌药和抗糖尿病药的反应。我们的结果表明，对缺氧和聚集的反应降低了葡萄糖的摄取，乳酸分泌，细胞呼吸和ATP的合成，这表明观察到的聚集为球体的细胞增殖减少是呼吸下调的结果。SVF球体的招募增加了球体的侵袭能力，但仅在最具攻击性的细胞中降低了呼吸作用。此外，聚集和缺氧降低了对代谢药物AICAR和二甲双胍以及化学治疗药物顺铂和紫杉醇的反应。我们的结果表明，细胞代谢的适应性可能有助于在非宽松条件下提高生存率，并且这些代谢变化可能为将来旨在提高转移性​​卵巢癌妇女生存率的干预措施提供目标。以及化疗药物顺铂和紫杉醇。我们的结果表明，细胞代谢的适应性可能有助于在非宽松条件下提高生存率，并且这些代谢变化可能为将来旨在提高转移性​​卵巢癌妇女生存率的干预措施提供目标。以及化疗药物顺铂和紫杉醇。我们的结果表明，细胞代谢的适应性可能有助于在非宽松条件下提高生存率，并且这些代谢变化可能为将来旨在提高转移性​​卵巢癌妇女生存率的干预措施提供目标。