Proinflammatory Cytokine IL-1β Promotes Tumor Growth of Lewis Lung Carcinoma by Induction of Angiogenic Factors: In Vivo Analysis of Tumor-Stromal Interaction

Abstract

Inflammatory conditions are associated with tumor development. IL-1β is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1β in tumor growth in vivo, we transduced the retroviral vector coding human IL-1β gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1β) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1β grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1β cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1β cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1β itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1β cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1β tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1β cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1β cells in vivo. These results indicated that secreting IL-1β into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

“…Interestingly, PGE 2 exerts similar prometastatic effects to colon cancer cells, stimulating cell migration (10,12). Furthermore, IL-1␣ enhanced TGF-␣-stimulated cell migration in a synergistic manner, mimicking the effect of PGE 2 (34). COX-2/PGE 2 signaling plays critical roles in neoangiogenesis; homozygous deletion of EP 2 R significantly reduces the number and size of intestinal polyps in APC ⌬716 mice that is associated with a reduction of VEGF expression, suggesting that PGE 2 /EP 2 signaling is critical for increased levels of VEGF in intestinal neoplasm (19 4 receptors are coupled to stimulatory G (G s ) proteins and signal through increased cAMP, whereas the EP 3 R is coupled to inhibitory G (G i ) proteins which inhibit the generation of cAMP.…”

“…IL-1 is known to stimulate tumor angiogenesis through increasing the secretion of angiogenic factors (34). Genetic disruption of the IL-1 genes results in significantly reduced secretion of VEGF by tumor cells (6).…”

Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

“…Altogether, these results indicate that tumors developing worse prognosis and identified by MMP-11 expression by intratumoral MICs, showed an up-regulation of inflammatory-related genes. These associations are relevant because these highly expressed genes have been associated with several biological mechanisms related to tumor progression [151][152][153][154][155][156][157]. It is also relevant the novel finding of the association between the expression of MMP-11 or TIMP-2 by the MICs at the tumor center and a high CD68/(CD3+CD20) ratio (macrophages (CD68 [158], since both proteins are the two principal factors defining the prometastatic phenotype of MICs in our previous studies [34,132,134,144].…”

The Effects of Epidural Anaesthesia and Analgesia on Natural Killer Cell Cytotoxicity and Cytokine Response in Patients with Epithelial Ovarian Cancer Undergoing Radical Resection

“…IL-1β has been shown to promote tumour growth and metastasis, and to induce tumourmediated immune suppression. 31 Evidence also suggests that IL-8 is critical to tumour neovascularity and progression. 32 In contrast, both IL-10 and IFN-γ are well known antitumour cytokines.…”