Breast Cancer, Chemokines, And Metastasis: A Search for Decoy Ligands of the CXCR4 Receptor

Abstract

Breast cancer (BC) is the leading cause of cancer-related deaths in young to middle-aged women worldwide. Moreover, the survival rate in BC-patients is only 20% when associated with metastatic disease. The high mortality rate observed in BC women with metastatic disease has precipitated a major challenge revealing an unmet need to develop new therapeutic strategies in treating metastatic cancer. One such approach has involved utilization of chemokines and their receptors as therapeutic targets for cancer metastasis. It has been established that a definitive correlation exists between overexpressed CXCR4 malignant cell receptors and cancer cell growth, invasion, and migration. It is also widely accepted that the CXCR4 receptor, complexed to its CXCL12 ligand, plays a major role in establishing migratory pathway gradients for cancer cells migrating to distant tissues/organ sites. It would follow that chemokine decoy ligands, such as peptide antagonists and inhibitors, could serve to induce receptor blockade and impede subsequent intracellular signaling. Such ligands, synthetic and natural, reportedly contribute to reducing cancer cell growth, invasion, adherence, and migration. The present commentary describes several existing synthetic CXCR4 receptor-ligand peptide antagonists and presents a strategy to develop naturally-occurring human protein-derived peptide candidates.

The paradoxical role of cytokines and chemokines at the tumor microenvironment: a comprehensive review

“…Notably, the challenges in creating and transferring novel chemokine-related target therapies are particularly exacerbated by the dearth of suitable animal models that accurately reflect the characteristics and behavior of human tumors [ 159 ]. Preclinical models are used in the clinical translation of cancer immunotherapy to prioritize drug targets and examine drug mechanisms of action, delivery strategies, treatment regimens, doses, and safety [ 160 ].…”

Alpha-Fetoprotein-derived Segments as Integrin Peptidomimetics for Potential Cancer Cell Targeting and Therapy: A Review and Commentary

“…In addition, ILPs such as GIP have been reported to induce apoptosis in radio-sensitized cultured lymphocytes [33]. Moreover, it has been reported that ADAM-22, a disintegrinlike metalloproteinase, is an active participant in the development of breast cancer resistance during endocrine hormone therapy in women [48][49][50]. With regard to this report, GIP administered to cultured MCF-7 human breast cancer cells was shown to down-regulate the expression of ADAM-22 by 30-fold as determined by a global RNA microarray analysis [44].…”

Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

“…Notably, the lack of appropriate animal models reflecting the features and behaviour of human cancers also contributes to the difficulties in developing and translating novel chemokine-related target therapies [175]. Clinical translation of cancer immunotherapy relies on preclinical models to prioritise drug targets and investigate mechanisms of action, delivery approaches, treatment schedule, dose and safety [176].…”