Extracellular matrix dysregulation in aging, calcification, and cancer diseases: insights into cellular senescence, inflammation, and novel therapeutic strategies

Nov 24, 2025International journal of biological sciences

Changes in the tissue scaffold linked to aging, hardening, and cancer: connections to cell aging, inflammation, and new treatments

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Abstract

The extracellular matrix (ECM) plays a crucial role in regulating cellular behavior and maintaining tissue homeostasis.

In healthy tissues, controlled ECM remodeling provides essential biochemical and mechanical cues.
Dysregulation of the ECM, driven by factors like chronic inflammation and cellular aging, can lead to fibrosis, calcification, and a pro-tumor environment.
Senescent cells contribute to ECM changes through a secretory process that promotes inflammation and degradation.
In cancer, ECM remodeling facilitates tumor progression and metastasis while also reducing the effectiveness of conventional therapies.
Aberrant ECM remodeling in cardiovascular diseases worsens tissue damage and hinders regeneration.
Emerging therapies aim to restore ECM balance through various strategies, including ECM-normalizing agents and stem cell approaches.

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This review underscores the dynamic role of the extracellular matrix (ECM) in regulating cellular behavior and maintaining tissue homeostasis, highlighting its pivotal involvement in aging, calcification, and cancer diseases. In healthy tissues, controlled ECM remodeling provides essential biochemical and mechanical cues, but dysregulation (driven by chronic inflammation, cellular senescence, and altered intercellular communication) leads to fibrosis, calcification, and the creation of a pro-tumorigenic microenvironment. Senescent cells contribute to these changes through senescence-associated secretory phenotype (SASP), which reinforces inflammation and matrix degradation, while extracellular vesicles (EVs) mediate intercellular signaling and further modulate ECM structure and function. In cancer, ECM remodeling not only facilitates tumor progression and metastasis by forming physical and biochemical barriers but also hinders the efficacy of conventional and immunotherapeutic interventions. Similarly, in cardiovascular diseases, aberrant ECM remodeling exacerbates tissue damage and impairs regenerative processes. Emerging therapeutic strategies aim to restore ECM homeostasis through targeted interventions, including ECM-normalizing agents, EV-based therapies, and stem cell approaches that modulate matrix composition to improve tissue repair. By elucidating the complex interplay between ECM dysfunction, cellular senescence, and chronic inflammation, this review highlights promising avenues for developing personalized treatments that address the underlying causes of age-related and tumorigenic pathologies, ultimately, the way to improved clinical outcomes.

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Extracellular matrix dysregulation in aging, calcification, and cancer diseases: insights into cellular senescence, inflammation, and novel therapeutic strategies

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