Growth regulated oncogene-alpha expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC receptor-2 dependent mechanism

Oncogene. 2000 Jul 20;19(31):3477-86. doi: 10.1038/sj.onc.1203687.

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

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / blood supply
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Transformed
  • Chemokine CXCL1
  • Chemokines, CXC*
  • Chemotactic Factors / biosynthesis
  • Chemotactic Factors / genetics
  • Chemotactic Factors / physiology*
  • Chemotaxis, Leukocyte / genetics*
  • DNA, Complementary / genetics
  • Growth Substances / biosynthesis
  • Growth Substances / genetics
  • Growth Substances / physiology*
  • Intercellular Signaling Peptides and Proteins*
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Lymphocytes, Tumor-Infiltrating / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / physiopathology
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / genetics*
  • Phenotype
  • Receptors, Chemokine / deficiency
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / physiology*
  • Receptors, Interleukin / deficiency
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / physiology*
  • Receptors, Interleukin-8B
  • Recombinant Fusion Proteins / physiology
  • Transfection
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / transplantation

Substances

  • Chemokine CXCL1
  • Chemokines, CXC
  • Chemotactic Factors
  • Cxcl1 protein, mouse
  • DNA, Complementary
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Receptors, Chemokine
  • Receptors, Interleukin
  • Receptors, Interleukin-8B
  • Recombinant Fusion Proteins