Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancer
Abstract Background 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 c...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-06-01
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| Series: | Aging and Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/aac2.12049 |
| _version_ | 1811294680505122816 |
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| author | Elizabeth I. Harper Tyvette S. Hilliard Emma F. Sheedy Preston Carey Paul Wilkinson Michael D. Siroky Jing Yang Elizabeth Agadi Annemarie K. Leonard Ethan Low Yueying Liu Arya Biragyn Christina M. Annunziata Mary Sharon Stack |
| author_facet | Elizabeth I. Harper Tyvette S. Hilliard Emma F. Sheedy Preston Carey Paul Wilkinson Michael D. Siroky Jing Yang Elizabeth Agadi Annemarie K. Leonard Ethan Low Yueying Liu Arya Biragyn Christina M. Annunziata Mary Sharon Stack |
| author_sort | Elizabeth I. Harper |
| collection | DOAJ |
| description | Abstract Background 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. Aim 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 ID8Trp53–/– OvCa cells showed enhanced IP dissemination in aged versus young mice. In vitro 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 in vivo 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. Conclusions 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 premetastatic niche contributing to enhanced OvCa metastatic success in the aged host. |
| first_indexed | 2024-04-13T05:21:02Z |
| format | Article |
| id | doaj.art-58408a16a910405f8e3c9cfe215b7ce4 |
| institution | Directory Open Access Journal |
| issn | 2643-8909 |
| language | English |
| last_indexed | 2024-04-13T05:21:02Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Aging and Cancer |
| spelling | doaj.art-58408a16a910405f8e3c9cfe215b7ce42022-12-22T03:00:44ZengWileyAging and Cancer2643-89092022-06-013211612910.1002/aac2.12049Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancerElizabeth I. Harper0Tyvette S. Hilliard1Emma F. Sheedy2Preston Carey3Paul Wilkinson4Michael D. Siroky5Jing Yang6Elizabeth Agadi7Annemarie K. Leonard8Ethan Low9Yueying Liu10Arya Biragyn11Christina M. Annunziata12Mary Sharon Stack13Department of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USADepartment of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USAHarper Cancer Research Institute University of Notre Dame Notre Dame Indiana USAHarper Cancer Research Institute University of Notre Dame Notre Dame Indiana USAHarper Cancer Research Institute University of Notre Dame Notre Dame Indiana USADepartment of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USADepartment of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USADepartment of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USADepartment of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USADepartment of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USADepartment of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USANational Institute on Aging Bethesda Maryland USANational Cancer Institute Bethesda Maryland USADepartment of Chemistry and Biochemistry University of Notre Dame Notre Dame Indiana USAAbstract Background 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. Aim 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 ID8Trp53–/– OvCa cells showed enhanced IP dissemination in aged versus young mice. In vitro 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 in vivo 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. Conclusions 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 premetastatic niche contributing to enhanced OvCa metastatic success in the aged host.https://doi.org/10.1002/aac2.12049agingcollagenmetastasisomentumovarian cancer |
| spellingShingle | Elizabeth I. Harper Tyvette S. Hilliard Emma F. Sheedy Preston Carey Paul Wilkinson Michael D. Siroky Jing Yang Elizabeth Agadi Annemarie K. Leonard Ethan Low Yueying Liu Arya Biragyn Christina M. Annunziata Mary Sharon Stack Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancer Aging and Cancer aging collagen metastasis omentum ovarian cancer |
| title | Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancer |
| title_full | Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancer |
| title_fullStr | Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancer |
| title_full_unstemmed | Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancer |
| title_short | Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancer |
| title_sort | another wrinkle with age aged collagen and intra peritoneal metastasis of ovarian cancer |
| topic | aging collagen metastasis omentum ovarian cancer |
| url | https://doi.org/10.1002/aac2.12049 |
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