Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer.

Pancreatic cancer (PC) has a poor prognosis, and current therapeutic strategies are ineffective in advanced diseases. We and others have shown the aberrant expression of CXCR2 and its ligands in PC development and progression. Our objective for this study was to evaluate the therapeutic utility of CXCR2/1 targeting using an small molecule antagonist, SCH-479833, in different PC preclinical murine models (syngeneic or xenogeneic). Our results demonstrate that CXCR2/1 antagonist had both antitumor and anti-metastatic effects in PC. CXCR2/1 antagonist treatment inhibited tumor cell proliferation, migration, angiogenesis, and recruitment of neutrophils, while it increased apoptosis. Treatment with the antagonist enhanced fibrosis, tumor necrosis, and extramedullary hematopoiesis. Together, these findings suggest that selectively targeting CXCR2/1 with small molecule inhibitors is a promising therapeutic approach for inhibiting PC growth, angiogenesis, and metastasis.

CXCR1: A Cancer Stem Cell Marker and Therapeutic Target in Solid Tumors.

Therapy resistance is a significant concern while treating malignant disease. Accumulating evidence suggests that a subset of cancer cells potentiates tumor survival, therapy resistance, and relapse. Several different pathways regulate these purported cancer stem cells (CSCs). Evidence shows that the inflammatory tumor microenvironment plays a crucial role in maintaining the cancer stem cell pool. Typically, in the case of the tumor microenvironment, inflammatory pathways can be utilized by the tumor to aid in tumor progression; one such pathway is the CXCR1/2 pathway. The CXCR1 and CXCR2 receptors are intricately related, with CXCR1 binding two ligands that also bind CXCR2. They have the same downstream pathways but potentially separate roles in the tumor microenvironment. CXCR1 is becoming more well known for its role as a cancer stem cell identifier and therapeutic target. This review elucidates the role of the CXCR1 axis as a CSC marker in several solid tumors and discusses the utility of CXCR1 as a therapeutic target.

Differential expression profile of CXC-receptor-2 ligands as potential biomarkers in pancreatic ductal adenocarcinoma.

The discovery of early detection markers of pancreatic cancer (PC) disease is highly warranted. We analyzed the expression profile of different CXC-receptor-2 (CXCR2) ligands in PC cases for the potential of biomarker candidates. Analysis of different PDAC microarray datasets with matched normal and pancreatic tumor samples and next-generation sequenced transcriptomics data using an online portal showed significantly high expression of CXCL-1, 3, 5, 6, 8 in the tumors of PC patients. High CXCL5 expression was correlated to poor PC patient survival. Interestingly, mRNA and protein expression analysis of human PC cell lines showed higher CXCL2, 3, and 5 expressions in cell lines derived from metastatic sites than primary tumors. Furthermore, we utilized immunohistochemistry (IHC) to evaluate the expression of CXCR2 ligands in the human PC tumors and observed positive staining for CXCL1, 3, and 8 with a higher average IHC composite score of CXCL3 in the PC tissue specimens than the normal pancreas. We also observed an increase in the expression of mouse CXCL1, 3, and 5 in the pre-cancerous lesions of tumors and metastasis tissues derived from the PDX-cre-LSL-KrasG12D mouse model. Together, our data suggest that different CXCR2 ligands show the potential of being utilized as a diagnostic biomarker in PC patients.