Comprehensive Analysis of CD44 in Colorectal Cancer: Molecular Mechanisms, Isoform Interactions, and Targeted Treatments to Address Tumorigenesis and Chemoresistance

Cluster of differentiation 44 (CD44), a versatile transmembrane glycoprotein, plays a crucial role in the progression, metastasis, and therapeutic resistance of colorectal cancer (CRC). This review clarifies CD44's essential function in CRC via connections with the extracellular matrix (ECM), particularly hyaluronic acid (HA), and important signaling pathways, such as Ras/mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). The overexpression of CD44, especially its variant isoforms (CD44v), is associated with aggressive tumor characteristics, increased cancer stem cell (CSC) traits, and unfavorable outcomes in CRC patients. CD44 enhances tumor cell attachment, movement, infiltration, and epithelial-mesenchymal transition, facilitating metastasis and resistance to chemotherapy. Its interactions with ECM elements and receptors, such as the epidermal growth factor receptor, enhance tumor growth and survival signaling. Therapeutic approaches aimed at CD44, such as monoclonal antibodies, small interfering RNAs, and nanoparticles targeting CD44 (e.g., CSA-SS-CXB@CPT, A@HAP), show encouraging antitumor effectiveness by interrupting CD44-HA interactions and the subsequent signaling pathways. Preclinical studies emphasize the benefits of pairing anti-CD44 therapies with PI3K/Akt or Wnt/β-catenin inhibitors to improve results. This review combines CD44's molecular mechanisms, isoform-specific functions, and CSC regulation in CRC, highlighting the potential as a biomarker and therapeutic target to enhance patient outcomes.