Regulation of chemokine expression in the tumor microenvironment

Abstract

Chemokines are chemotactic cytokines critical for homeostatic and inflammation-induced trafficking of leukocytes during immune responses, hematopoesis, wound healing, and tumorigenesis. Despite three decades of intensive study of the chemokine network, the molecular mechanisms regulating chemokine expression during tumor growth are not well understood. In this review, we focus on the role of chemokines in both tumor growth and anti-tumor immune responses and on molecular mechanisms employed by tumor cells to regulate chemokine expression in the tumor microenvironment. Multiple mechanisms used by tumors to regulate chemokine production, including those revealed by very recent studies (such as DNA methylation or post-translational nitrosylation of chemokines) are discussed. Concluding the review, we discuss how understanding of these regulatory mechanisms can be used in cancer therapy to suppress tumor growth and/or to promote immune-mediated eradication of tumors.

FIG. 1:

Treatment of CXCL9-deficient tumor cells with demethylating drug decitabine (DAC) restores IFN-g–inducible CXCL9 mRNA expression and protein production. Upper panel: CXCL9-deficient variants of MCA205 fibrosarcoma or B16 melanoma were cultured with IFN-g alone or with IFN-g and DAC for 24 h. Total cell RNA was extracted from cell cultures and the expression of CXCL9 mRNA was tested by quantitative RT-PCR. The expression level of mRNA isolated from tumor cells not stimulated with IFN-g was arbitrarily set at 1.0 and used to determine the relative expression levels in the IFN-g-stimulated samples. Fold increase of CXCL9 mRNA levels in cells treated with DAC vs. non-treated cells is shown. Lower panels: CXCL9-deficient variants of MCA205 fibrosarcoma or B16 melanoma were cultured with IFN-g alone or with IFN-g and different concentrations of DAC for 72 h. Culture supernatants were collected and tested for CXCL9 protein by CXCL9-specific ELISA..

FIG. 2:

Mechanisms employed by tumor cells to regulate chemokine expression in the tumor microenvironment. Figure depicts currently known mechanisms used by tumors to regulate the expression of chemokines and their receptors. The examples of transcriptional regulation include (a) direct effects of oncoproteins (Ras), tumor-associated transcription factors (STAT-3), hormones (estrogen) or prostaglandin E2 (PGE2) on chemokine promoter that results in the activation (↑) or inhibition (↓) of chemokine expression and (b) inhibition of chemokine expression through DNA methylation. Post-transcriptional regulation is mediated through modulating stability of chemokine mRNA by transcription factors (HuR) or oncoproteins (LMP-1). Post-translational regulation of chemokine functions can be mediated by chemical modification of chemokine structure (nitrosylation by reactive nitrogen species (RNS) produced by tumor cells) or by cleavage of chemokine by serine proteases (CD13, CD26). Availability of chemokine may be decreased through degradation of chemokine protein by proteases produced in the tumor microenvironment.