Abstract
Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.
Highlights
Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients
Chemokines are grouped into four subfamilies—CC, XC, CXC, and CX3C—and are functionally classified into two groups—homeostatic and inflammatory subtypes [3]
An exosome biomarker meta-analysis of 921 breast cancer patients from 11 studies showed that CXCR4 expression together with Her2, Kinase insert Domain Receptor (KDR), CD49d, and CD44 characterized the exosomal protein pattern associated with tumor recurrence or distant organ metastasis [63]
Summary
The tumor microenvironment (TME) is a dynamic heterocellular niche that affects cancer fate. CXCR4 is a cancer stem cell marker in PDAC [57], prostate cancer [58], and renal cell carcinoma [59] Another meta-analysis of 25 selected articles involving 3796 patients with colorectal cancer confirmed that CXCR4 expression is related to tumor–node–metastasis (TNM) stage, tumor differentiation, liver metastasis, lymph node metastasis, distant metastasis, and reduced survival [60]. An exosome biomarker meta-analysis of 921 breast cancer patients from 11 studies showed that CXCR4 expression together with Her, Kinase insert Domain Receptor (KDR), CD49d, and CD44 characterized the exosomal protein pattern associated with tumor recurrence or distant organ metastasis [63]. In bladder, lung squamous, pancreatic, prostate and rectum carcinomas, CXCR4 showed significantly higher mRNA expression levels in normal cells adjacent to tumor tissue compared to cancer cells (Figure 1b). The characterization of the CXCR4 genomic landscape may represent a key and promising element in the identification of relevant biomarkers for prognosis, clinicopathological classification, and precision therapy in cancer
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