A glitch in the matrix: Age‐dependent changes in the extracellular matrix facilitate common sites of metastasis

Abstract

People over 55 years old represent the majority of cancer patients and suffer from increased metastatic burden compared to the younger patient population. As the aging population increases globally, it is prudent to understand how the intrinsic aging process contributes to cancer progression. As we age, we incur aberrant changes in the extracellular matrix (ECM) of our organs, which contribute to numerous pathologies, including cancer. Notably, the lung, liver, and bone represent the most common sites of distal metastasis for all cancer types. In this review, we describe how age-dependent changes in the ECM of these organs influence cancer progression. Further, we outline how these alterations prime the premetastatic niche and why these may help explain the disparity in outcome for older cancer patients.

Another wrinkle with age: Aged collagen and intra‐peritoneal metastasis of ovarian cancer

“…Collagen has a half‐life of several decades, so aged microenvironmental collagen can accumulate far more posttranslational modifications relative to either young or newly synthesized collagen. This is supported by the increase in AGEs, observed in purified collagen from aged hosts, that crosslink fibrils and reduce susceptibility to remodeling 40,47,51,41 . In contrast, enhanced peri‐tumor collagen remodeling in vivo was observed in young mice relative to aged using SHG/B‐CHP analysis, consistent with collagen fibril degradation experiments showing that young collagen is more susceptible to collagenolysis.…”

“…Aged omenta also have increased collagen content and collagen crosslinks that result in thicker banding and higher intensity of the SHG signal. Collagen fibers that are tightly bound together, as seen here in aged omenta, likely have fewer accessible sites for enzymatic cleavage 47,41 . Previous studies of metastatic microenvironments have shown that tumor cells remodel the ECM to generate TACS, including increased alignment of collagen fibers, increased collagen deposition, and increased crosslinking 26–28,41 .…”

“…Collagen fibers that are tightly bound together, as seen here in aged omenta, likely have fewer accessible sites for enzymatic cleavage. 47,41 Previous studies of metastatic microenvironments have shown that tumor cells remodel the ECM to generate TACS, including increased alignment of collagen fibers, increased collagen deposition, and increased crosslinking. [26][27][28]41 Indeed, OvCa patients whose omental tumors exhibited enhanced tissue stiffness together with expression of a panel of ECM-associated genes and proteins, including COL1A1, were found to have poor overall survival.…”

“…These modifications include covalent crosslinks between molecules, produced either by a nonenzymatic glycation process that forms advanced glycation end products (AGEs) or enzymatically catalyzed by lysyl oxidase 38,39 . These posttranslational modifications can also impact collagen structure, reducing tissue elasticity and decreasing susceptibility to remodeling by MMPs 40,41 . As tumor cell interaction with omental collagen is a key event in OvCa metastasis, 5–9 in the current study, we evaluated the hypothesis that age‐related changes in collagen in the ovarian tumor microenvironment promote OvCa metastatic success in the aged host.…”

“…38,39 These posttranslational modifications can also impact collagen structure, reducing tissue elasticity and decreasing susceptibility to remodeling by MMPs. 40,41 As tumor cell interaction with omental collagen is a key event in OvCa metastasis, [5][6][7][8][9] in the current study, we evaluated the hypothesis that age-related changes in collagen in the ovarian tumor microenvironment promote OvCa metastatic success in the aged host.…”