What is the role of the secretome (all proteins secreted by cells) in disease and health?

The Secretome: A Critical Mediator of Disease and Health

The secretome—comprising all proteins secreted by cells including growth factors, cytokines, extracellular matrix proteins, proteases, and extracellular vesicles—serves as a fundamental communication network that drives both physiological processes and pathological conditions, with its dysregulation directly contributing to cardiovascular disease, neurodegeneration, cancer progression, and aging-related tissue dysfunction. 1, 2

Core Components and Biological Functions

The secretome encompasses multiple protein classes that orchestrate intercellular communication:

• Growth factors and cytokines that regulate cell proliferation, differentiation, and survival across tissue types 2
• Extracellular matrix proteins including collagen, fibronectin, and laminin that provide structural support and biochemical signaling 1
• Proteases and their inhibitors that remodel tissue architecture and regulate protein activation 3, 2
• Extracellular vesicles (exosomes and microvesicles) containing proteins, RNA, and metabolites that mediate long-distance cellular communication 1
• Metabolic proteins that influence systemic metabolism and energy homeostasis 1, 2

Role in Cardiovascular Health and Disease

In cardiac tissue, the secretome demonstrates therapeutic potential through paracrine mechanisms:

• Stem cell-derived secretomes mediate cardiac functional improvement through pro-angiogenic pathways, macrophage phenotype modulation, and anti-fibrotic effects rather than through cell engraftment itself 1
• Extracellular vesicles from cardiovascular progenitors outperformed the parent cells in improving cardiac function in heart failure models, demonstrating the primacy of secreted factors over cellular therapy 1
• Controlled release of secretome components from biomaterial scaffolds prolongs therapeutic benefit in post-myocardial infarction heart failure, with demonstrated reduction in infarct size and improved ejection fraction 1

The Senescence-Associated Secretory Phenotype (SASP)

The secretome undergoes pathological transformation during cellular senescence, becoming a primary driver of age-related disease:

• SASP proteins include pro-inflammatory cytokines, chemokines, growth factors, and matrix proteases that accumulate as senescent cells resist apoptosis and persist in tissues 1
• SASP-mediated tissue degeneration directly causes osteoarthritis, pulmonary fibrosis, atherosclerosis, diabetes, and Alzheimer's disease through chronic inflammation and disruption of tissue homeostasis 1, 4
• Cells expressing p16^Ink4a^ with elevated SASP show independent correlation with reduced muscle strength and impaired walking performance, demonstrating functional consequences of secretome dysregulation 1
• SASP proteins damage the extracellular matrix and inhibit progenitor cell function, preventing tissue repair and regeneration 1

Cancer Biology and Therapeutic Implications

The cancer secretome actively promotes tumor progression through multiple mechanisms:

• Triple-negative breast cancer secretomes drive tumor growth, angiogenesis, epithelial-mesenchymal transition, drug resistance, invasion, and premetastatic niche formation 3
• Secreted proteins enable communication between tumor cells and stromal cells, creating a permissive microenvironment for cancer progression 3
• The cancer secretome represents a rich source of therapeutic targets and diagnostic biomarkers due to accessibility in blood and other body fluids 3, 5, 2

Neurological Health and Disease

Recent advances demonstrate the secretome's critical role in neural function:

• Astrocyte-derived secretomes contain neurotrophic factors including FAM3C and KITLG that enhance neurite outgrowth, protect neuronal viability, and promote neural progenitor proliferation 6
• Astrocyte secretome dysregulation contributes to non-cell autonomous neurotoxicity in neurodegenerative diseases, making it a therapeutic target 6

Clinical Detection and Measurement

The secretome provides accessible biomarkers for disease monitoring:

• Blood-based proteomics can detect secreted proteins with mass spectrometry and antibody-based immunoassays providing concentration estimates 2
• Tissue-specific secretomes can be sampled through body fluids including uterine fluid, cerebrospinal fluid, and synovial fluid, offering less invasive alternatives to tissue biopsy 1, 2
• Extracellular vesicles isolated from blood contain proteins, RNA, DNA, and metabolites that reflect the biochemical status of parent cells and disease states 1

Critical Methodological Considerations

When studying or interpreting secretome data:

• Contamination by non-secreted proteins (particularly albumin and structural proteins) represents a major analytical challenge requiring careful isolation methods 1
• Serum-containing culture media introduces exogenous proteins that confound secretome analysis; serum-free conditions or biorthogonal labeling methods are necessary 1, 6
• Post-translational modifications including glycosylation and phosphorylation create protein variants that may serve as disease-specific biomarkers 1
• Temporal dynamics matter: secretome composition changes with cellular state, disease stage, and environmental conditions 1, 5

Therapeutic Applications

The secretome offers multiple therapeutic avenues:

• Acellular biomaterials delivering secretome components avoid cell survival concerns while providing localized, sustained release of therapeutic factors 1
• Injectable hydrogels containing growth factors or complete secretomes reduce infarct size and improve cardiac function in animal models and early human trials 1
• Targeting pathological secretomes (such as SASP) with senolytic drugs or secretome-modifying agents represents an emerging therapeutic strategy 1

Common Pitfalls to Avoid

• Do not assume all secreted proteins enter systemic circulation; many are retained locally at the tissue of expression or in the extracellular matrix 2
• Avoid interpreting secretome changes without considering cellular composition shifts in heterogeneous tissues, as different cell types contribute distinct secretome profiles 1
• Do not overlook the distinction between constitutive and regulated secretion, as stress, inflammation, and disease states dramatically alter secretome composition 1, 5
• Recognize that extracellular vesicles are only one component of the total secretome; soluble proteins remain functionally important 1