Role of chemokines in tumor growth

Hypoxia poses many problems to the treatment of cancer. Hypoxic tumors are more resistant to chemotherapy and radiation. In addition, hypoxia induces a number of genes responsible for increased invasion, aggressiveness, and metastasis of tumors. The augmented metastatic potential due to hypoxia-mediated gene expression is discussed in this section. Particular attention is given to recent studies of specific genes involved in the key steps of metastasis, including extracellular matrix interactions, migration, and proliferation.

Hypoxia, gene expression, and metastasis

Chemokines mediate numerous physiological and pathological processes related primarily to cell homing and migration. The chemokine CXCL12, also known as stromal cell-derived factor-1, binds the G-protein-coupled receptor CXCR4, which, through multiple divergent pathways, leads to chemotaxis, enhanced intracellular calcium, cell adhesion, survival, proliferation, and gene transcription. CXCR4, initially discovered for its involvement in HIV entry and leukocytes trafficking, is overexpressed in more than 23 human cancers. Cancer cell CXCR4 overexpression contributes to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance. CXCR4 antagonism has been shown to disrupt tumor–stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden. As such, CXCR4 is a target not only for therapeutic intervention but also for noninvasive monitoring of disease progression and therapeutic guidance. This review provides a comprehensive overview of the biological involvement of CXCR4 in human cancers, the current status of CXCR4-based therapeutic approaches, as well as recent advances in noninvasive imaging of CXCR4 expression.

The intricate role of CXCR4 in cancer.

The chemokine receptor CXCR4 belongs to the large superfamily of G protein-coupled receptors and has been identified to play a crucial role in a number of biological processes, including the trafficking and homeostasis of immune cells such as T lymphocytes. CXCR4 has also been found to be a prognostic marker in various types of cancer, including leukemia and breast cancer, and recent evidence has highlighted the role of CXCR4 in prostate cancer. Furthermore, CXCR4 expression is upregulated in cancer metastasis, leading to enhanced signaling. These observations suggest that CXCR4 is important for the progression of cancer. The CXCR4-CXCL12 (stromal cell-derived factor 1 (SDF-1)) axis has additionally been identified to have a role in normal stem cell homing. Interestingly, cancer stem cells also express CXCR4, indicating that the CXCR4-SDF-1 axis may direct the trafficking and metastasis of these cells to organs that express high levels of SDF-1, such as the lymph nodes, lungs, liver, and bone. This review focuses on the current knowledge of CXCR4 regulation and how deregulation of this protein may contribute to the progression of cancer.

https://www.springer.com/cda/content/document/cda_downloaddocument/9781603272667-c1.pdf?SGWID=0-0-45-734104-p173747353

CXCR4 and Cancer

https://digital.csic.es/bitstream/10261/41074/1/BLOOD12.pdf

The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression.

Tumor cell migration involved in metastases is a tightly regulated, nonrandom process. Chemokines have been identified as critical molecules guiding cell migration. We performed a prospective study to analyze a possible association between the expression of chemokine receptors CXCR3 and CXCR4 by primary melanoma and clinical outcome. Forty primary melanomas were available for analysis; 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 by melanoma cells. At initial diagnosis, 5 patients had subclinical lymph node involvement and after a median follow-up time of 32 months, 2 additional patients developed regional lymph node metastases and 5 patients developed distant metastases. The expression of CXCR4, but not CXCR3, by melanoma cells in primary lesions was significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate. Our study underscores the value of CXCR4 expression as a useful marker for predicting outcome in patients with localized melanoma. In addition, our findings support that, among chemokine receptors, CXCR4 might be an appropriate therapeutic target for adjuvant therapy in patients at risk for metastatic disease.

Isabel Treviño

Papers

Clinical significance of CXCR3 and CXCR4 expression in primary melanoma.