Expression of CXCL8 and Its Receptors in Malignant Melanoma
Expression of CXCL8 and Its Receptors in Malignant Melanoma
We examined the expression of CXCL8 (interleukin-8), its receptors, CXCR1 and CXCR2, and vessel density in human melanoma by immunohistochemical analysis of tumors from different Clark levels, depths, and thicknesses. Expression of CXCL8 and CXCR2 was lower in Clark level I and II specimens than in level III through V specimens and metastases. CXCR1 expression was observed ubiquitously in the majority of human melanoma tumor specimens irrespective of disease state, with the highest intensity in Clark level III specimens. We observed a significant difference in CXCL8 and CXCR2 expression between thin (≤0.75 mm) and thick (>0.75 mm) melanomas and between thin and metastatic lesions. Positive correlations were observed between Clark level and CXCL8 or CXCR2 and between thickness and CXCR2 expression. We found no correlation between vessel density and Clark level or thickness. Our data suggest that expression of CXCL8 and CXCR2 contributes to aggressive growth and metastasis in human malignant melanoma. Consistent with the transition from radial to vertical growth phase melanoma, expression of CXCL8 and its receptor, CXCR2, may be key in the switch to an aggressive, more metastatic phenotype.
The incidence and mortality of melanoma is rising faster than any other cancer in men and second only to lung cancer in women, and the American Cancer Society predicts there will be about 7,770 deaths due to melanoma during 2005. The chance of developing melanoma increases with age, but it affects all age groups and is one of the most common cancers in young adults. Most melanomas progress through an initial radial growth phase, or in situ melanoma, to a more aggressive vertical growth phase that exhibits growth in the mesenchyme and in the epithelium. Clark described the initial steps of primary neoplasia as levels I through III, and invasive neoplasms are categorized as levels IV and V. Similarly in 1970, Breslow related the importance of thickness and its impact on survival. Today the Clark classification and overall thickness are important prognostic factors.
Melanoma specimens and cell lines derived from them have been to shown to express a variety of chemokines, including CXCL8 (interleukin-8), CXCL1 through CXCL3 (MGSA/Groα-γ), CCL2 (monocyte chemotactic protein-1), and CCL5 (RANTES). Thus, there are implications for these factors in the control of the progression of malignant disease and secondary organ metastasis. CXCL8 can influence the processes of tumor progression and metastasis because it has been shown to be an autocrine growth factor, to induce angiogenesis, and to influence migration of melanoma cells through the binding and activation of its receptors. Reports from our laboratory and others suggest that metastasis of cutaneous malignant melanoma is associated with constitutive expression of CXCL8.
Two receptors for CXCL8, the type A CXCL8 receptor (CXCL8RI or CXCR1) and type B CXCL8 receptor (CXCL8RII or CXCR2) have been shown to bind CXCL8 with high affinity. CXCR1 is selective for CXCL8, whereas CXCR2 also interacts with other chemokines. CXCR1 and CXCR2 are expressed on keratinocytes, fibro-blasts, and endothelial and melanoma cells and also have been implicated in the angiogenic response and in the migration of neutrophils and lymphocytes. Norgauer et al found low expression of CXCR2 on normal human melanocytes, which was up-regulated after treatment with tumor necrosis factor α, with subsequent enhancement of proliferation in response to CXCL8, whereas CXCR1 expression was not detectable.
CXCL8 has been shown to be an important angiogenic factor, and the CXCR2 receptor has been demonstrated to be the putative angiogenic receptor. In addition, expression of CXCR1 and CXCR2 has been demonstrated on endothelial cells. However, the association of CXCL8 and its receptors with the progression of melanoma remains uncertain. To determine the functional role of CXCL8 and to elucidate the individual role of each receptor in the progression of malignant melanoma, expression of CXCL8 and its receptors, CXCR1 and CXCR2, on malignant melanoma cells was examined in a sequential manner.
We examined the expression of CXCL8 (interleukin-8), its receptors, CXCR1 and CXCR2, and vessel density in human melanoma by immunohistochemical analysis of tumors from different Clark levels, depths, and thicknesses. Expression of CXCL8 and CXCR2 was lower in Clark level I and II specimens than in level III through V specimens and metastases. CXCR1 expression was observed ubiquitously in the majority of human melanoma tumor specimens irrespective of disease state, with the highest intensity in Clark level III specimens. We observed a significant difference in CXCL8 and CXCR2 expression between thin (≤0.75 mm) and thick (>0.75 mm) melanomas and between thin and metastatic lesions. Positive correlations were observed between Clark level and CXCL8 or CXCR2 and between thickness and CXCR2 expression. We found no correlation between vessel density and Clark level or thickness. Our data suggest that expression of CXCL8 and CXCR2 contributes to aggressive growth and metastasis in human malignant melanoma. Consistent with the transition from radial to vertical growth phase melanoma, expression of CXCL8 and its receptor, CXCR2, may be key in the switch to an aggressive, more metastatic phenotype.
The incidence and mortality of melanoma is rising faster than any other cancer in men and second only to lung cancer in women, and the American Cancer Society predicts there will be about 7,770 deaths due to melanoma during 2005. The chance of developing melanoma increases with age, but it affects all age groups and is one of the most common cancers in young adults. Most melanomas progress through an initial radial growth phase, or in situ melanoma, to a more aggressive vertical growth phase that exhibits growth in the mesenchyme and in the epithelium. Clark described the initial steps of primary neoplasia as levels I through III, and invasive neoplasms are categorized as levels IV and V. Similarly in 1970, Breslow related the importance of thickness and its impact on survival. Today the Clark classification and overall thickness are important prognostic factors.
Melanoma specimens and cell lines derived from them have been to shown to express a variety of chemokines, including CXCL8 (interleukin-8), CXCL1 through CXCL3 (MGSA/Groα-γ), CCL2 (monocyte chemotactic protein-1), and CCL5 (RANTES). Thus, there are implications for these factors in the control of the progression of malignant disease and secondary organ metastasis. CXCL8 can influence the processes of tumor progression and metastasis because it has been shown to be an autocrine growth factor, to induce angiogenesis, and to influence migration of melanoma cells through the binding and activation of its receptors. Reports from our laboratory and others suggest that metastasis of cutaneous malignant melanoma is associated with constitutive expression of CXCL8.
Two receptors for CXCL8, the type A CXCL8 receptor (CXCL8RI or CXCR1) and type B CXCL8 receptor (CXCL8RII or CXCR2) have been shown to bind CXCL8 with high affinity. CXCR1 is selective for CXCL8, whereas CXCR2 also interacts with other chemokines. CXCR1 and CXCR2 are expressed on keratinocytes, fibro-blasts, and endothelial and melanoma cells and also have been implicated in the angiogenic response and in the migration of neutrophils and lymphocytes. Norgauer et al found low expression of CXCR2 on normal human melanocytes, which was up-regulated after treatment with tumor necrosis factor α, with subsequent enhancement of proliferation in response to CXCL8, whereas CXCR1 expression was not detectable.
CXCL8 has been shown to be an important angiogenic factor, and the CXCR2 receptor has been demonstrated to be the putative angiogenic receptor. In addition, expression of CXCR1 and CXCR2 has been demonstrated on endothelial cells. However, the association of CXCL8 and its receptors with the progression of melanoma remains uncertain. To determine the functional role of CXCL8 and to elucidate the individual role of each receptor in the progression of malignant melanoma, expression of CXCL8 and its receptors, CXCR1 and CXCR2, on malignant melanoma cells was examined in a sequential manner.