A comprehensive review of the literature on CD10: its function, clinical application, and prospects

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TL;DR

CD10 is a zinc-dependent metalloprotease involved in cardiovascular, immune, and neurological processes, and its dysregulation is linked to cancers, Alzheimer's disease, heart failure, obesity, and diabetes. The review highlights CD10's dual role as both a tumor suppressor and promoter depending on context, and its inhibitors (e.g., sacubitril/valsartan) show clinical promise in heart failure and other conditions. Understanding CD10's tissue-specific functions and signaling pathways is critical for developing targeted therapies.

Full summary

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**Background:** CD10 (neprilysin, NEP) is a zinc-dependent metalloprotease expressed on cell surfaces and in bodily fluids. It degrades numerous bioactive peptides, including enkephalins, substance P, natriuretic peptides, endothelin, and amyloid-beta (Aβ). Its roles span cardiovascular regulation, immune modulation, pain signaling, fetal development, and aging. Dysregulation of CD10 is implicated in hematologic and solid tumors, Alzheimer's disease (AD), heart failure (HF), obesity, type 2 diabetes, and inflammatory arthritis. This review consolidates recent findings on CD10's molecular functions, disease associations, and therapeutic targeting.

**Methods:** The authors conducted a comprehensive literature review, synthesizing studies from 1975 to 2023. They searched for publications on CD10's physicochemical properties, tissue expression, molecular mechanisms, and roles in various diseases. Emphasis was placed on studies examining CD10 expression in tumors (hematologic and nonhematologic), AD, cardiovascular diseases, obesity/diabetes, inflammatory arthritis, stem cells, and COVID-19. The review also covers preclinical and clinical studies of CD10 inhibitors.

**Key Results:** - **Hematologic tumors:** CD10 expression in B-lineage ALL correlates with favorable prognosis; co-expression of CD34 and CD10 indicates significantly better outcomes. CD10 is a critical diagnostic marker for subclassifying acute leukemias and non-Hodgkin lymphomas. - **Nonhematologic tumors:** CD10 overexpression is linked to poor prognosis in breast, prostate, colorectal, head and neck, and esophageal cancers. In prostate cancer, CD10 expression correlates with aggressive phenotype and lower survival. In colorectal cancer, CD10 expression is associated with liver metastases. In breast cancer, stromal CD10 expression indicates poor prognosis and is linked to cancer stem cell phenotype. CD10+ GPR77+ cancer-associated fibroblasts secrete IL-6/8 and protect breast cancer cells from chemotherapy. - **Alzheimer's disease:** CD10 is a primary Aβ-degrading enzyme. Its levels are decreased in AD brains, particularly in hippocampus and temporal gyrus. Overexpressing CD10 in transgenic mice reduces Aβ deposits and prevents amyloid plaque formation. Exosomal CD10 from masseter muscle can travel to hippocampus via trigeminal nerve, suggesting chewing may elevate brain CD10. - **Cardiovascular diseases:** CD10 degrades natriuretic peptides, bradykinin, and adrenomedullin. Soluble CD10 levels inversely correlate with ventricular function in hypertrophic cardiomyopathy. Lower membrane CD10 on neutrophils/granulocytes is associated with worse HF prognosis. Sacubitril/valsartan (ARNI) improves outcomes in HF with reduced ejection fraction (HFrEF) and was FDA-approved in 2015. - **Obesity and diabetes:** Elevated CD10 levels are associated with insulin resistance and adipogenesis. CD10-deficient mice develop obesity and glucose intolerance. Green tea increases CD10 expression in kidney and intestine, reducing body fat in Berlin fat mice. Urinary CD10 is increased in diabetic patients and may predict CKD progression. - **Inflammatory arthritis:** CD10 degrades substance P, exerting anti-inflammatory effects. Infrapatellar fat pad-derived MSCs overexpressing CD10 reverse synovitis and fibrosis in vivo. - **Stem cells:** CD10 is a marker for hematopoietic and tissue stem cells. CD10-high adipose-derived stem cells show superior differentiation. CD10+ perivascular cells exhibit enhanced proliferation and osteogenic potential. In cancer stem cells, CD10 upregulates CSC-related genes (CD44, ALDH1, BMI1, NANOG, OCT4, SOX2) and promotes chemoresistance. - **COVID-19:** CD10+ B cell levels inversely correlate with COVID-19 severity. Neutrophil CD10 expression is low in all COVID-19 patients. CD10 may mitigate pulmonary inflammation by cleaving fMLP and regulating bradykinin and TGF-β pathways. - **Therapeutic targeting:** CD10 inhibitors include candoxatril (early HF), sacubitril/valsartan (ARNI, approved for HFrEF), thiorphan (accelerates wound healing in diabetic mice), UK-414,445 (enhances genital blood flow), and opiorphin peptides (improve sperm motility and erectile function). CD10 inhibitors also show potential in pain management, diabetes complications, and cancer, but most remain preclinical.

**Clinical Implications:** CD10 is a versatile therapeutic target with applications in HF, AD, obesity, diabetes, wound healing, and reproductive health. Sacubitril/valsartan is the most successful CD10 inhibitor in clinical use. However, CD10 inhibition may cause adverse effects such as angioedema, bronchial reactivity, and potential predisposition to AD. Further research is needed to clarify CD10's context-dependent roles and to develop safe, effective inhibitors for non-cardiovascular indications.