Abstract
Growth Regulated Oncogene-alpha (GRO-alpha) is an autocrine growth factor in melanoma and is a member of the C-X-C family of chemokines which promote chemotaxis of granulocytes and endothelia through binding to CXC Receptor 2. We found previously that variants of murine squamous cell carcinoma PAM 212 which grow and metastasize more rapidly in vivo constitutively express increased levels of murine GRO-alpha, designated mGRO-alpha, or KC. We have examined the possible role of mGRO-alpha expression in malignant progression of squamous cell carcinoma PAM 212 in homologous BALB/c and BALB CXC Receptor-2 deficient mice. Transfection of the PAM 212 cell line which exhibits low expression of GRO-alpha and malignant potential with a pActin-KC vector encoding mGRO-alpha enabled isolation of PAM-KC expressing cell lines. These PAM-KC transfectants displayed an increased rate of growth and metastasis in BALB/c mice, similar to the highly malignant phenotype observed in spontaneously occurring metastatic variants. Furthermore, the PAM-KC tumors showed an increase in infiltration of host leukocytes and CD31+ blood vessels, consistent with increased CXC chemokine activity. The increased growth of PAM-KC cells was attenuated in CXCR-2 deficient mice, indicating that the increased growth was dependent in part upon host cells responsive to the CXC chemokine. Together, these results show that a CXC chemokine such as GRO-alpha can promote malignant growth of murine squamous cell carcinoma by a host CXCR-2 dependent pathway. Oncogene (2000) 19, 3477 - 3486
Highlights
Squamous cell carcinomas (SCC) may arise in the skin, upper aerodigestive tract, lung and cervix, and are a signi®cant cause of cancer morbidity and mortality in the US and worldwide
We have shown that expression of CXC chemokine murine GRO-a (mGRO-a) (KC) by squamous carcinoma cells increases tumor growth and metastasis in a model in which cytokines and receptors expressed by tumor cells and the host are homologous
The malignant phenotype resulting from expression of mGRO-a in the PAM-KC transfectants was similar to that observed in the highly malignant variants of PAM that had been derived from experimental metastases and constitutively expressed elevated levels of mGRO-a mRNA and protein (Chen et al, 1997; Van Waes et al, 1999)
Summary
Squamous cell carcinomas (SCC) may arise in the skin, upper aerodigestive tract, lung and cervix, and are a signi®cant cause of cancer morbidity and mortality in the US and worldwide. GRO-a is an autocrine growth factor identi®ed in melanoma (Balentien et al, 1991), and is a member of the C-XC family of chemokines which promote chemotaxis of granulocytes and endothelia (Strieter et al, 1996). MGRO-a shares major sequence homology and leukocyte chemotactic activity (Oquendo et al, 1989; Bozic et al, 1995) with both human GRO-a and IL-8, for which independent murine counterparts have not been identi®ed. Human IL-8 and GRO-a have been reported to induce chemotaxis of neutrophils and neovascular endothelial cells (Smith et al, 1994; Strieter et al, 1996). While mGRO-a has been shown to induce neutrophil chemotaxis (Bozic et al, 1995), the angiogenic activity of murine GRO-a has not been reported. CXCR2 is expressed on neutrophils and endothelia (Strieter et al, 1996)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
