Epithelial-Mesenchymal Transition and Tumor Microenvironment
Epithelial-Mesenchymal Transition and Tumor Microenvironment
As depicted in Figure 1, IL-8 released by tumor cells undergoing EMT could play several roles in the context of tumor progression by: maintaining the mesenchymal, invasive phenotype of tumor cells that have undergone EMT via an autocrine loop; exerting a paracrine effect on adjacent epithelial tumor cells in order to induce EMT; enhancing angiogenesis and potentially attracting immune cells to the site of the tumor, thus creating an inflammatory environment that could further favor tumor dissemination; and metastasis.
Among the cellular targets of IL-8 are the endothelial cells, which can be induced to proliferate and migrate in response to IL-8 signaling, therefore resulting in neovascularization. In a study with non-small-cell lung carcinoma cells forced into EMT via SNAIL overexpression, the enhanced secretion of the chemokine IL-8 led to enhanced angiogenesis and tumor growth in vivo. The SNAIL-mediated increase in tumor burden was efficiently abrogated with anti-IL-8RB neutralizing antibodies, a result that indicated the fundamental role of IL-8 in SNAIL-mediated tumor progression. These results also demonstrated that tumor cells undergoing EMT have the potential to directly affect their surrounding stroma via the secretion of soluble factors. A similar example was reported with MCF7 breast cancer cells undergoing EMT via Twist overexpression, which grew as highly vascularized tumors in vivo as a result of their increased secretion of the angiogenic factor VEGF.
In addition to its effects on endothelial cells, IL-8 is also known to be a strong chemotactic factor for neutrophils. The enhanced secretion of IL-8 by tumor cells undergoing EMT could also lead to enhanced recruitment of neutrophils, which, in turn, have been shown to exert various protumorigenic and prometastatic functions. For example, in a study conducted with a K-RAS-mutated lung adenocarcinoma model, enhanced secretion of the chemokines MIP-2 and CXCL1, murine homologs of IL-8, was linked to the recruitment of neutrophils to the site of the tumor. Tumor-associated neutrophils, in turn, have been shown to assist in tumor progression by different means. For example, tumor-associated neutrophils have been shown to directly facilitate the escape of melanoma tumor cells from the circulation into lung tissues via ICAM-1-mediated binding of tumor cells to the surface of neutrophils. Moreover, tumor progression can be assisted by tumor-associated neutrophils via the secretion of multiple proteinases, including MMPs, which could remodel the ECM and favor tumor migration. Although several studies have shown enhanced secretion of IL-8 in the context of tumor EMT, so far there have been no studies specifically investigating the leukocytic infiltrates of tumors characterized by EMT in contrast to those with a fully epithelial phenotype.
Tumor cells undergoing EMT are not the only source of IL-8 in the microenvironment of a progressive tumor. As previously mentioned, various cellular components of the tumor stroma, including fibroblasts, endothelial cells and immune cells, can secrete IL-8 in response to various stress factors. Of particular interest are reports demonstrating that fibroblasts undergoing chemotherapy- or radiation-induced DNA damage and senescence, but not nonsenescent fibroblasts, are able to induce EMT and invasiveness in epithelial cancer cells. It was shown that this effect was mediated via the secretion of biologically active proteins by senescent fibroblasts, designated as the senescence-associated secretory phenotype, and, in particular, via secretion of IL-6 and IL-8. These observations indicate that the tumor stroma has the potential to promote tumor progression via secretion of multiple factors involved in intercellular signaling, acting in a paracrine fashion on the epithelial tumor compartment. As a result, IL-8 released by the stroma could directly influence tumor cell proliferation, migration, invasion and EMT, and, as more recently shown, could help tumor cells to evade stress-induced apoptosis.
Potential Effects of IL-8 on the Tumor Microenvironment
As depicted in Figure 1, IL-8 released by tumor cells undergoing EMT could play several roles in the context of tumor progression by: maintaining the mesenchymal, invasive phenotype of tumor cells that have undergone EMT via an autocrine loop; exerting a paracrine effect on adjacent epithelial tumor cells in order to induce EMT; enhancing angiogenesis and potentially attracting immune cells to the site of the tumor, thus creating an inflammatory environment that could further favor tumor dissemination; and metastasis.
Among the cellular targets of IL-8 are the endothelial cells, which can be induced to proliferate and migrate in response to IL-8 signaling, therefore resulting in neovascularization. In a study with non-small-cell lung carcinoma cells forced into EMT via SNAIL overexpression, the enhanced secretion of the chemokine IL-8 led to enhanced angiogenesis and tumor growth in vivo. The SNAIL-mediated increase in tumor burden was efficiently abrogated with anti-IL-8RB neutralizing antibodies, a result that indicated the fundamental role of IL-8 in SNAIL-mediated tumor progression. These results also demonstrated that tumor cells undergoing EMT have the potential to directly affect their surrounding stroma via the secretion of soluble factors. A similar example was reported with MCF7 breast cancer cells undergoing EMT via Twist overexpression, which grew as highly vascularized tumors in vivo as a result of their increased secretion of the angiogenic factor VEGF.
In addition to its effects on endothelial cells, IL-8 is also known to be a strong chemotactic factor for neutrophils. The enhanced secretion of IL-8 by tumor cells undergoing EMT could also lead to enhanced recruitment of neutrophils, which, in turn, have been shown to exert various protumorigenic and prometastatic functions. For example, in a study conducted with a K-RAS-mutated lung adenocarcinoma model, enhanced secretion of the chemokines MIP-2 and CXCL1, murine homologs of IL-8, was linked to the recruitment of neutrophils to the site of the tumor. Tumor-associated neutrophils, in turn, have been shown to assist in tumor progression by different means. For example, tumor-associated neutrophils have been shown to directly facilitate the escape of melanoma tumor cells from the circulation into lung tissues via ICAM-1-mediated binding of tumor cells to the surface of neutrophils. Moreover, tumor progression can be assisted by tumor-associated neutrophils via the secretion of multiple proteinases, including MMPs, which could remodel the ECM and favor tumor migration. Although several studies have shown enhanced secretion of IL-8 in the context of tumor EMT, so far there have been no studies specifically investigating the leukocytic infiltrates of tumors characterized by EMT in contrast to those with a fully epithelial phenotype.
Tumor cells undergoing EMT are not the only source of IL-8 in the microenvironment of a progressive tumor. As previously mentioned, various cellular components of the tumor stroma, including fibroblasts, endothelial cells and immune cells, can secrete IL-8 in response to various stress factors. Of particular interest are reports demonstrating that fibroblasts undergoing chemotherapy- or radiation-induced DNA damage and senescence, but not nonsenescent fibroblasts, are able to induce EMT and invasiveness in epithelial cancer cells. It was shown that this effect was mediated via the secretion of biologically active proteins by senescent fibroblasts, designated as the senescence-associated secretory phenotype, and, in particular, via secretion of IL-6 and IL-8. These observations indicate that the tumor stroma has the potential to promote tumor progression via secretion of multiple factors involved in intercellular signaling, acting in a paracrine fashion on the epithelial tumor compartment. As a result, IL-8 released by the stroma could directly influence tumor cell proliferation, migration, invasion and EMT, and, as more recently shown, could help tumor cells to evade stress-induced apoptosis.
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