Harper Elizabeth I, Hilliard Tyvette S, Sheedy Emma F, Carey Preston, Wilkinson Paul, Siroky Michael D, Yang Jing, Agadi Elizabeth, Leonard Annemarie K, Low Ethan, Liu Yueying, Biragyn Arya, Annunziata Christina M, Stack M Sharon
Department of Chemistry & Biochemistry, Notre Dame, IN.
Harper Cancer Research Institute, Notre Dame, IN.
Aging Cancer. 2022 Jun;3(2):116-129. doi: 10.1002/aac2.12049. Epub 2022 Apr 19.
Age is the most significant risk factor for ovarian cancer (OvCa), the deadliest gynecologic malignancy. Metastasizing OvCa cells adhere to the omentum, a peritoneal structure rich in collagen, adipocytes, and immune cells. Ultrastructural changes in the omentum and the omental collagen matrix with aging have not been evaluated.
The aim of this study was to test the hypothesis that age-related changes in collagen in the ovarian tumor microenvironment promote OvCa metastatic success in the aged host.
METHODS/RESULTS: Young (3-6 months) and aged mice (20-23 months) were used to study the role of aging in metastatic success. Intra-peritoneal (IP) injection of ID8 ovarian cancer cells showed enhanced IP dissemination in aged young mice. assays using purified collagen demonstrated reduced collagenolysis of aged fibers, as visualized using scanning electron microscopy (SEM) and quantified with a hydroxyproline release assay. Omental tumors in young and aged mice showed similar collagen deposition; however enhanced intra-tumoral collagen remodeling was seen in aged mice probed with a biotinylated collagen hybridizing peptide (CHP). In contrast, second harmonic generation (SHG) microscopy showed significant differences in collagen fiber structure and organization in omental tissue and SEM demonstrated enhanced omental fenestration in aged omenta. Combined SHG and Alexa Fluor-CHP microscopy demonstrated that peri-tumoral collagen was remodeled more extensively in young mice. This collagen population represents truly aged host collagen, in contrast to intra-tumoral collagen that is newly synthesized, likely by cancer associated fibroblasts (CAFs).
Our results demonstrate that tumors in an aged host can grow with minimal collagen remodeling, while tumors in the young host must remodel peri-tumoral collagen to enable effective proliferation, providing a mechanism whereby age-induced ultrastructural changes in collagen and collagen-rich omenta establish a permissive pre-metastatic niche contributing to enhanced OvCa metastatic success in the aged host.
年龄是卵巢癌（OvCa）最显著的风险因素，卵巢癌是最致命的妇科恶性肿瘤。发生转移的OvCa细胞会附着在大网膜上，大网膜是一种富含胶原蛋白、脂肪细胞和免疫细胞的腹膜结构。大网膜及大网膜胶原基质随年龄增长发生的超微结构变化尚未得到评估。
本研究旨在验证以下假设：卵巢肿瘤微环境中与年龄相关的胶原蛋白变化会促进老年宿主中OvCa转移成功。
方法/结果：使用年轻（3 - 6个月）和老年小鼠（20 - 23个月）来研究衰老在转移成功中的作用。腹腔内（IP）注射ID8卵巢癌细胞显示，老年小鼠的癌细胞腹腔内播散增强。使用纯化胶原蛋白进行的实验表明，老年纤维的胶原溶解减少，这通过扫描电子显微镜（SEM）观察并通过羟脯氨酸释放试验进行定量。年轻和老年小鼠的大网膜肿瘤显示出相似的胶原蛋白沉积；然而，在用生物素化胶原杂交肽（CHP）检测的老年小鼠中，肿瘤内胶原重塑增强。相比之下，二次谐波产生（SHG）显微镜显示大网膜组织中胶原纤维结构和组织存在显著差异，SEM显示老年大网膜的开窗现象增强。结合SHG和Alexa Fluor - CHP显微镜显示，年轻小鼠肿瘤周围的胶原重塑更为广泛。与肿瘤内可能由癌症相关成纤维细胞（CAF）新合成的胶原蛋白相比，这种胶原群体代表真正的老年宿主胶原蛋白。
我们的结果表明，老年宿主中的肿瘤可以在最小程度的胶原重塑下生长，而年轻宿主中的肿瘤必须重塑肿瘤周围的胶原以实现有效增殖，这提供了一种机制，即年龄诱导的胶原蛋白和富含胶原蛋白的大网膜的超微结构变化建立了一个允许的前转移微环境，有助于老年宿主中OvCa转移成功增强。
