Protocadherins in solid tumors: mechanisms, clinical implications, and therapeutic horizons

Protocadherins (PCDHs) are diverse cell adhesion molecules that play a pivotal role in cellular communication, tissue organization, and regulation of critical cellular processes. Hereafter, PCDHs' denotes the entire protocadherin family; isoform-specific isoforms (e.g., PCDH7, PCDH10) are referred to without pluralization unless contextually require. Accumulating evidence has highlighted their significant contribution to the pathogenesis and progression of solid tumors, and the expression dysregulation thereof is intricately linked to tumorigenesis, metastatic potential, and clinical outcomes. Specific PCDH isoforms have tumor-suppressive functions, whereas others appear to drive tumor growth and invasion. These effects are mediated through diverse mechanisms, including modulation of cell adhesion dynamics, regulation of key signaling pathways, and interactions with components of the tumor microenvironment. Recently, the importance of cell adhesion molecules in cancer biology has been highlighted, with PCDHs emerging as a functionally diverse protein family that is critically involved in tumorigenesis and malignant progression. This review aimed to comprehensively summarize the roles of PCDHs in solid tumors and explore the translational potential to improve cancer care. A more comprehensive understanding of the multifaceted roles of PCDHs in solid tumors may pave the way for innovative cancer treatment strategies and improved patient outcomes. Collectively, we highlight the biological significance of PCDHs in solid tumor pathology and their potential translational relevance to oncology. Additionally, this review summarizes the expression patterns of PCDHs in various solid tumors and their impact on tumor occurrence, progression, and metastasis, and explores their potential as diagnostic and therapeutic targets. It should be noted that many studies to date report only correlative evidence; direct functional and causal validation is generally lacking.