Abstract
Simple SummaryChemokines are central players in cancer and can be post-translationally modified by dipeptidyl peptidase IV (DPPIV)/CD26. This can have different effects on chemokine function, ranging from reduced, unchanged to enhanced activity. CD26 is differentially expressed in tumors, which affects the dominant chemokine isoform present in the tumor microenvironment. In this review, we aim to recapitulate the current knowledge on the interplay between CD26 and chemokine activity in cancer.Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer. Both tumor-promoting and -impeding roles have been ascribed to chemokines, which they exert in a direct or indirect manner. An important post-translational modification that regulates chemokine activity is the NH2-terminal truncation by peptidases. CD26 is a dipeptidyl peptidase (DPPIV), which typically clips a NH2-terminal dipeptide from the chemokine. With a certain degree of selectivity in terms of chemokine substrate, CD26 only recognizes chemokines with a penultimate proline or alanine. Chemokines can be protected against CD26 recognition by specific amino acid residues within the chemokine structure, by oligomerization or by binding to cellular glycosaminoglycans (GAGs). Upon truncation, the binding affinity for receptors and GAGs is altered, which influences chemokine function. The consequences of CD26-mediated clipping vary, as unchanged, enhanced, and reduced activities are reported. In tumors, CD26 most likely has the most profound effect on CXCL12 and the interferon (IFN)-inducible CXCR3 ligands, which are converted into receptor antagonists upon truncation. Depending on the tumor type, expression of CD26 is upregulated or downregulated and often results in the preferential generation of the chemokine isoform most favorable for tumor progression. Considering the tight relationship between chemokine sequence and chemokine binding specificity, molecules with the appropriate characteristics can be chemically engineered to provide innovative therapeutic strategies in a cancer setting.
Highlights
Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer
We summarize the knowledge on the effect of chemokine processing by CD26 in cancer
Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a continuous abnormal trafficking of hematopoietic stem cells (HSCs) and hematopoietic progenitor cell (HPC) into the blood, which results in extramedullary hematopoiesis
Summary
Tumor development and progression are driven by the acquirement of sequential aberrant characteristics within the tumor microenvironment. Malignant and non-malignant cells in the tumor stroma secrete environmental cues to sculpt the tumor micromilieu and support tumor growth, progression, and evasion from the host’s immune defense. Chemokines are a large family of small chemotactic cytokines whose main function relies in regulation of the trafficking of leukocytes via G protein-coupled receptors (GPCRs) expressed on target cells. Aside from acting as leukocyte recruiters, chemokine function in cancer has broadened extensively. They can influence cancer progression directly by supporting constitutive growth, survival, invasion, and metastatic spread or indirectly by stimulating or impeding angiogenesis and defining the immune response by specific leukocyte subset recruitment to shape primary and metastatic tumor sites. Depending on the chemokine involved, they can either promote or impede tumor progression or even a combination of both depending on the tumor type. Based on the positioning of the conserved NH2 -terminal cysteine residues, chemokines are classified into four subclasses, namely CXC, CC, CX3 C, and C chemokines [3]
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