CD248 facilitates tumor growth via its cytoplasmic domain

BMC Cancer. 2011 May 8;11:162. doi: 10.1186/1471-2407-11-162.

Abstract

Background: Stromal fibroblasts participate in the development of a permissive environment for tumor growth, yet molecular pathways to therapeutically target fibroblasts are poorly defined. CD248, also known as endosialin or tumor endothelial marker 1 (TEM1), is a transmembrane glycoprotein expressed on activated fibroblasts. We recently showed that the cytoplasmic domain of CD248 is important in facilitating an inflammatory response in a mouse model of arthritis. Others have reported that CD248 gene inactivation in mice results in dampened tumor growth. We hypothesized that the conserved cytoplasmic domain of CD248 is important in regulating tumor growth.

Methods: Mice lacking the cytoplasmic domain of CD248 (CD248CyD/CyD) were generated and evaluated in tumor models, comparing the findings with wild-type mice (CD248WT/WT).

Results: As compared to the response in CD248WT/WT mice, growth of T241 fibrosarcomas and Lewis lung carcinomas was significantly reduced in CD248CyD/CyD mice. Tumor size was similar to that seen with CD248-deficient mice. Conditioned media from CD248CyD/CyD fibroblasts were less effective at supporting T241 fibrosarcoma cell survival. In addition to our previous observation of reduced release of activated matrix metalloproteinase (MMP)-9, CD248CyD/CyD fibroblasts also had impaired PDGF-BB-induced migration and expressed higher transcripts of tumor suppressor factors, transgelin (SM22α), Hes and Hey1.

Conclusions: The multiple pathways regulated by the cytoplasmic domain of CD248 highlight its potential as a therapeutic target to treat cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Becaplermin
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cytoplasm / metabolism
  • Endothelial Cells / metabolism
  • Fibroblasts / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / physiopathology*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Platelet-Derived Growth Factor / pharmacology
  • Proto-Oncogene Proteins c-sis
  • Receptor, Notch3
  • Receptors, Notch / metabolism
  • Repressor Proteins / genetics
  • Signal Transduction / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inducing Agents
  • Antigens, CD
  • Basic Helix-Loop-Helix Transcription Factors
  • Hairy, HRT1 protein
  • Microfilament Proteins
  • Muscle Proteins
  • Neoplasm Proteins
  • Notch3 protein, mouse
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Receptor, Notch3
  • Receptors, Notch
  • Repressor Proteins
  • transgelin
  • tumor endothelial marker 1, mouse
  • Becaplermin