Approximately, 30 000 men die from prostate cancer (PCa) every year in the United States, mainly due to the metastasis. Thus, the key events associated with PCa metastasis are under rigorous investigation, with recent studies showing that preparation of pre-metastatic niches (PMN) in distant organs is an important step. However, the molecular basis for PMN preparation is still unclear. Hypoxia in primary tumors promotes aggressiveness; however, its precise role in metastasis is not clear. We recently reported that exosomes secreted by PCa cells under hypoxia promote stemness and invasiveness in naïve PCa cells; however, whether these extracellular vesicles also influence PMN remains unknown. In the present study, we isolated exosomes from human PCa PC3 cells under normoxic (21% O2 , exosomes secreted under normoxic condition [ExoNormoxic ]) and hypoxic (1% O2 , exosomes secreted under hypoxic condition [ExoHypoxic ]) conditions, and characterized their effect (10 µg exosomes, intraperitoneal (IP) treatment every 48 hours for 4 weeks) on key biomarkers associated with PMN in nude mice. Whole animal fluorescence imaging showed that ExoHypoxic treatment promotes matrix metalloproteinases (MMPs) activity in several putative metastatic sites. Histological studies confirmed that ExoHypoxic treatment enhanced the level of MMP2, MMP9, and extracellular matrix proteins (fibronectin and collagen) as well as increased the number of CD11b+ cells at selective PMN sites. Furthermore, proteomic profiling of exosomes by liquid chromatography/mass spectrometry identified cargo proteins in ExoNormoxic and ExoHypoxic as well as distinct canonical pathways targeted by them. These results suggest that exosomes secreted by PCa cells under hypoxia plausibly remodel distant PMN, and thus, could be a potential target to control metastatic PCa.

中文翻译：

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缺氧时前列腺癌细胞分泌的外泌体在转移前的利基处促进基质金属蛋白酶活性。

在美国，每年大约有3万名男性死于前列腺癌（PCa），这主要是由于转移引起的。因此，与PCa转移有关的关键事件正在严格研究中，而最近的研究表明，在远处器官中准备转移前的生态位（PMN）是重要的一步。但是，PMN制备的分子基础仍然不清楚。原发性肿瘤的缺氧会促进侵袭性。然而，其在转移中的确切作用尚不清楚。我们最近报道说，低氧条件下PCa细胞分泌的外泌体可促进幼稚PCa细胞的干性和侵袭性。然而，这些细胞外囊泡是否也会影响PMN尚不清楚。在本研究中，我们从常氧（21％O2，在常氧条件下[ExoNormoxic]和低氧（1％O2，在低氧条件下[ExoHypoxic]分泌的外泌体）分泌的外泌体，并表征其作用（10μg外泌体，每48小时进行一次腹膜内（IP）治疗，持续4周）裸鼠中与PMN相关的生物标志物。整个动物的荧光成像显示，低氧处理可以在几个假定的转移部位促进基质金属蛋白酶（MMP）的活性。组织学研究证实，低氧处理提高了MMP2，MMP9和细胞外基质蛋白（纤连蛋白和胶原蛋白）的水平，并增加了PMN选择性部位CD11b +细胞的数量。此外，通过液相色谱/质谱法对外泌体进行蛋白质组学分析，鉴定出ExoNormoxic和ExoHypoxic中的货物蛋白，以及它们靶向的独特经典途径。这些结果表明，低氧条件下PCa细胞分泌的外泌体似乎可以重塑远处的PMN，因此可能成为控制转移性PCa的潜在靶标。