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 collagen matrix with aging have not been evaluated.

Advanced Glycation End Products as a Potential Target for Restructuring the Ovarian Cancer Microenvironment: A Pilot Study

“…AGEs crosslink collagen and have been shown to block collagenolysis [ 7 ]. We have previously observed an increase in AGE content in isolated aged murine tail collagen relative to collagen from young mice, but omental collagen has not yet been investigated [ 5 ]. To examine AGE content in the intact omental tissue, second harmonic generation (SHG) imaging in conjunction with 2-photon excitation fluorescence (TPEF) microscopy using anti-AGE antibodies was employed.…”

“…We have previously demonstrated that omental collagen from aged mice displayed significantly enhanced anisotropy with an increase in long linear fibers and thick banding relative to omenta from young mice [ 5 ], and similar results are seen in Figure 1 a. To evaluate the potential impact of AGE breakers on omental ultrastructure and function, young (Y, 3–6 month) or aged (A, 20–23 month) mice were placed into one of four cohorts ( Figure 2 a): young + vehicle control, aged + vehicle control, aged + ALT-711, or aged + 2C8.…”

“…To evaluate potential changes in omental collagen ultrastructure in mice receiving AGE breaker treatment, omenta were imaged using SHG to visualize collagen structure. In this cohort, the thick banding of collagen is apparent in the “aged+vehicle” cohort relative to the “young+vehicle” ( Figure 3 a) [ 5 ]. Visual examination shows that the 2C8-treated mice more closely resembled the aged control cohort, with remaining thick banding ( Figure 3 a).…”

“…There are documented age-related changes in adipose, collagen, and immune populations that can impact OvCa metastasis [ 4 ]. Specifically, we have previously shown age-related changes in collagen ultrastructure, as well as the presence of advanced glycation end products (AGEs) in collagen isolated from aged mice [ 5 ].…”

“…These undergo an Amadori rearrangement and are oxidized to form AGEs, which can then be further modified to form crosslinks between collagen molecules, such as pentosidine or glucosepane [ 6 ]. The resulting inter-molecular crosslinks alter collagen structure and function by reducing the efficacy of collagenolytic matrix metalloproteinases (MMPs), thereby creating a more compact collagen structure that can disrupt the collagen meshwork in organs such as the skin and omentum [ 5 , 7 , 8 , 9 , 10 , 11 , 12 ]. As a non-enzymatic process, AGEs tend to form on long-lived, low-turnover proteins such as collagen and are present at higher rates in older individuals, as well as diabetic patients who have higher levels of blood glucose [ 13 , 14 , 15 , 16 ].…”