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Chemokines in the Biology of Lung Cancer

      This is a brief review of some of the mechanisms by which members of the large family of chemotactic cytokines (known as chemokines) participate in critical features of lung cancer biology.
      Chemokines are a family of small (8–12 kDa) cytokines consisting of four subfamilies defined by the configuration of the first two of four conserved cysteine residues (C, CC, CXC, and CXXXC families).
      • Rossi D
      • Zlotnik A
      The biology of chemokines and their receptors.
      Chemokines were initially studied for their ability to recruit specific subpopulations of leukocytes. However, research shows that many if not most of the members of the CC and CXC chemokine families are involved in mediating critical features of tumor biology, such as cell growth, angiogenesis, and metastasis, in addition to regulating tumor immunity. In this review, we briefly outline some of the mechanisms by which chemokines participate in two aspects of tumor biology, angiogenesis and metastasis.
      The CXC chemokines can be divided into members that promote angiogenesis (all of which have in common the glutamic acid-leucine-arginine sequence, the “ELR motif,” immediately preceding the first cysteine in the NH3-terminus; the ELR-CXC chemokines), and those that can directly inhibit angiogenesis (which, interestingly, are the inter-feron-inducible CXC chemokines CXCL9, CXCL10, and CXCL11). These angiostatic CXC chemokines may mediate many of the antiangiogenic and antitumor immune effects of interferons, a phenomenon referred to as “immunoangiostasis” by Strieter et al.
      • Strieter RM
      • Belperio JA
      • Burdick MD
      • et al.
      CXC Chemokines: angiogenesis, immunoangiostasis, and metastases in lung cancer.
      This dichotomy in the CXC chemokine family makes them unique among cytokines that regulate angiogenesis. We and others have shown that the ELR-CXC chemokines are major sources of angiogenic activity in non-small cell lung cancer, and that their expression in tumor homogenates correlates strongly with the vascularity of the corresponding tissue section.
      • Arenberg DA
      • Keane MP
      • DiGiovine B
      • et al.
      Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer.
      • Arenberg DA
      • Kunkel SL
      • Polverini PJ
      • et al.
      Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice.
      • Smith DR
      • Polverini PJ
      • Kunkel SL
      • et al.
      Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma.
      • White ES
      • Flaherty KR
      • Carskadon S
      • et al.
      Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis.
      Many studies have shown that a transcription factor, nuclear factor kappa-B (NFκB), is constitutively activated in cancer cells.
      • Higgins KA
      • Perez JR
      • Coleman TA
      • et al.
      Antisense inhibition of the p65 subunit of NF-kappaB blocks tumorigenicity and causes tumor regression.
      This NFκB activity in lung cancer cells is critical to the constitutive production of angiogenic CXC chemokines by malignant cells.
      • Xu L
      • Xie K
      • Mukaida N
      • et al.
      Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells.
      Importantly, nonmalignant cells also play a role in promoting angiogenesis. Macrophages and fibroblasts within the tumor are also activated (both by cell-matrix adhesive interactions and by soluble factors present within the tumor) to produce significant quantities of angiogenic CXC chemokines.
      • White ES
      • Livant DL
      • Markwart S
      • et al.
      Monocyte-fibronectin interactions, via a5b1 integrin, induce expression of CXC chemokine-dependent angiogenic activity.
      • White ES
      • Strom SRB
      • Wys NL
      • et al.
      Non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity.
      • Anderson IC
      • Mari SE
      • Broderick RJ
      • et al.
      The angiogenic factor interleukin 8 is induced in non-small cell lung cancer/pulmonary fibroblast cocultures.
      A critical report by Addison and colleagues showed that the endothelial receptor through which CXC chemokines induce angiogenesis is CXCR2.
      • Addison CL
      • Daniel TO
      • Burdick MD
      • et al.
      The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity.
      • Keane MP
      • Belperio JA
      • Xue YY
      • et al.
      Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer.
      In summary, ELR-CXC chemokines are an important source of angiogenic activity in lung cancer, and their expression is the net result of secretion by both malignant cells and infiltrating “normal” cells in the tumor stroma (Figure 1 A).
      Figure thumbnail gr1
      FIGURE 1(A) Angiogenic CXC chemokines (bullet shaped) derived from both malignant cells and tumor-infiltrating stromal cells induce angiogenesis by binding to CXCR2 present on tumor endothelium. (B) Stromal cell-derived factor 1 (now known as CXCL12) is constitutively produced in lymph nodes, liver, bone marrow, and the adrenal gland. This results in preferential “recruitment” to these organs of circulating tumor cells that express CXCR4.
      One of the more intriguing recent findings in this field is the discovery that specific chemokine ligand-receptor pairs dictate the organ-specific metastatic patterns of both breast and lung cancer.
      • Muller A
      • Homey B
      • Soto H
      • et al.
      Involvement of chemokine receptors in breast cancer metastasis.
      • Phillips RJ
      • Burdick MD
      • Lutz M
      • et al.
      The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases.
      In lung cancer, Phillips and colleagues showed that non-small cell lung cancer tumors and cell lines express the chemokine receptor CXCR4. Interestingly, CXCL12, the ligand for CXCR4, is constitutively expressed in the same tissues to which lung cancers preferentially metastasize (Figure 1 B). Antibody-mediated inhibition of CXCR4 in a mouse model of lung cancer dramatically reduced the incidence of tumor metastases.
      • Phillips RJ
      • Burdick MD
      • Lutz M
      • et al.
      The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases.
      This topic covers only a small proportion of the extensive overlap between the disciplines of chemokine and tumor biology. Chemokines can also act as growth factors
      • Balentien EJ
      • Han H
      • Thomas HG
      • et al.
      Recombinant expression, biochemical characterization, and biological activities of the human MGSA/gro protein.
      • Luan J
      • Shattuck-Brandt R
      • Haghnegahdar H
      • et al.
      Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression.
      and regulators of tumor immunity.
      • Strieter RM
      • Belperio JA
      • Burdick MD
      • et al.
      CXC Chemokines: angiogenesis, immunoangiostasis, and metastases in lung cancer.
      For a more in-depth review, see Balkwill.
      • Balkwill F
      Cancer and the chemokine network.
      The fundamental role(s) of chemokine ligand-receptor interactions in tumor biology suggests that targeting this biology is an important potential therapeutic opportunity for lung cancer. Therapeutic opportunities include approaches that target chemokines by blocking the proangiogenic chemokine receptor CXCR2 and/or the metastasis-promoting ligand receptor pair CXCL12/CXCR4. In addition, the interferon-inducible chemokines CXCL9, CXCL10, and CXCL11 should be explored as therapeutic agents themselves for their angiostatic and immunologic potential (immunoangiostasis of tumors). Each of these strategies has a sound rationale supported by current animal models and awaits further exploration at the level of human trials.

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