Glycation of the Extracellular Matrix (ECM) is not merely a phenomenon of tissue hardening, but is closely linked to cancer growth, invasion, and drug resistance. In particular, an ECM in which Advanced Glycation End-products (AGEs) have accumulated can alter the tumor microenvironment (TME), potentially affecting the efficacy of cytotoxic anticancer drugs, targeted therapies, and immune checkpoint inhibitors.
The extracellular matrix (ECM) plays a critical role in regulating tumor progression, immune cell infiltration, drug penetration, and therapeutic resistance. Increasing evidence suggests that ECM remodeling, fibrosis, tissue stiffness, and advanced glycation end-product (AGE) accumulation can substantially influence the efficacy of cytotoxic chemotherapy, targeted therapies, and immune checkpoint inhibitors.
A major limitation of many preclinical cancer models is that they may not fully recapitulate the complex ECM characteristics observed in human cancers. In naturally occurring tumors, the ECM evolves over years or decades under the influence of aging, chronic inflammation, metabolic dysregulation, oxidative stress, and glycation, leading to progressive fibrosis, increased stiffness, and AGE accumulation. In contrast, the ECM in most experimental xenograft and genetically engineered mouse models develops over a much shorter period and generally exhibits lower levels of age-related glycation and matrix remodeling.
These biological differences may contribute, at least in part, to the frequently observed discrepancy between preclinical efficacy and clinical outcomes, often referred to as the “animal-to-clinic translational gap.” Consequently, preclinical models incorporating aging, diabetes, or spontaneously arising tumors may provide a more clinically relevant platform for evaluating therapies designed to modulate the tumor microenvironment and ECM.
Based on this rationale, CBHI has conducted long-term retrospective analyses and exploratory studies investigating the potential role of SAC and SAC-SG in combination with conventional anticancer modalities. These observations suggest that combining SAC- or SAC-SG-based approaches with cytotoxic chemotherapy, targeted therapies, or immune checkpoint inhibitors may warrant further investigation as a strategy to enhance therapeutic responses through modulation of the tumor microenvironment. However, prospective mechanistic studies and controlled clinical trials are required to validate these findings and establish causality.
- Increased collagen cross-linking
- Increased ECM stiffness
- Decreased drug diffusion within the tissue
- Increased hypoxia
- Increased inflammatory cytokines
- Activation of AGE-RAGE signaling
Consequently, an environment favorable for cancer cell survival is formed.
- 5-Fluorouracil
- Oxaliplatin
- Paclitaxel
Increased Physical Barrier
Glycated ECM becomes denser, which can reduce drug penetration.
- Gastric Cancer
- Pancreatic Cancer
In breast cancer, the denser the ECM, the more difficult it is for drugs to reach the center of the tumor.
AGE-RAGE activity can inhibit apoptosis by activating the following pathways:
- NF-κB
- PI3K/AKT
- MAPK
- Decreased sensitivity to anticancer drugs
- Increased resistance
- Trastuzumab
- Osimertinib
- Ramucirumab
Glycated ECM increases integrin signaling, activating:
- FAK
- Src
- YAP/TAZ
In this case, cancer cells can survive through other pathways even if the original target signal is blocked.
That is:
- HER2 blockade → activation of bypass signals
- EGFR blockade → ECM-integrin signal compensation
This can occur.
- Pembrolizumab
- Nivolumab
Reduced Tumor Infiltration by Immune Cells
Glycated ECM can limit the infiltration of CD8 T cells into the tumor through:
- Formation of physical barriers
- Increased fibrosis
- Activation of CAF
- Increased TGF-β
AGE-RAGE activity is associated with:
Increases in IL-6, TNF-α, and TGF-β,and can induce increases in M2 macrophages and Tregs.
Consequently, there is a possibility that the effectiveness of immune checkpoint inhibitors may be reduced.
An interesting point is that MMPs are not always bad.
Appropriate ECM remodeling can aid in:
- The removal of ECM where AGEs have accumulated
- The remodeling of new ECM
Conversely, excessive MMP activity can promote metastasis, so balance is important.
Ca²⁺ can influence the following processes:
- Integratin signaling
- FAK activation
- MMP secretion
- Fibroblast activation
- Immune cell function
Therefore, judging that there is a sufficient possibility that calcium homeostasis influences ECM remodeling, we conducted in vitro tests.
Ultimately, data were obtained showing that SAC calcium has a strong inhibitory effect on MMPs in in vitro tests. In other words, since SAC inhibits ECM glycosylation, it is expected that anticancer drugs and immune cells will be able to reach cancer cells effectively, and research is being conducted continuously.
