Organ-specific Microenvironments Research Articles

Role of the host microenvironment on the expression of VEGF-subtypes in squamous cell carcinoma

The phenotypic characteristics and function of microvascular endothelium differs from tissue to tissue because of the organ specific microenvironment. Even the neovasculature in tumors differs depending upon tumor location. These findings indicate that local regulatory pathways modulate endothelial-cell growth and -function in a tissue specific manner. This might be mediated by novel tissue-specific regulators or the tissue specific regulation of known proteins. One of the major proangiogenic factors is VEGF. Its importance for tumor vascularisation and growth has been shown in several studies. VEGF is expressed in several subtypes and its impact on initial tumor growth and tumor progression has been discussed. Many of these results have been obtained by xenotransplantation studies in mice. The influence of the mouse microenvironment on the VEGF-subtype expression has not been previously analyzed. In the present study we analyzed the impact of the nude mouse microenvironment on the expression of the VEGF-subtypes after subcutaneous xenotransplantation. Our study was performed on seven squamous cell carcinoma (SCC) cell lines. We analyzed by quantitative PCR the mRNA-expression levels and the proportion of the subtypes -121, -165, -189, and of VEGF-total of established xenotransplanted tumors and compared them to the cell lines prior to transplantation. We found high VEGF-165 fractions in the cell lines leading to fast growing, large tumors. The proportion of the VEGF-isoforms remaining in the cell lines and xenotransplanted tumors were generally unchanged, but an overall decrease of VEGF by about 50% was observed. We conclude that the VEGF-subtypes expressed by the transplanted tumors are not differentially regulated by the nude mouse subcutaneous microenvironment and that the tumor growth characteristics are not dependent on VEGF-subtype regulation of the host.

Proteolytic Cleavage of the CD44 Adhesion Molecule in Multiple Human Tumors

Cell surface adhesion molecules are crucial for the development and/or pathogenesis of various diseases including cancer. CD44 has received much interest as a major adhesion molecule that is involved in tumor progression. We have previously demonstrated that the ectodomain of CD44 undergoes proteolytic cleavage by membrane-associated metalloproteases in various tumor cell lines. The remaining membrane-bound CD44 cleavage product can be detected using antibodies against the cytoplasmic domain of CD44 (anti-CD44cyto antibody). However, the cleavage of CD44 in primary human tumors has not been investigated. Using Western blots with anti-CD44cyto antibody to assay human tumor tissues, we show that the CD44 cleavage product can be detected in 58% (42 of 72) of gliomas but not in normal brain. Enhanced CD44 cleavage was also found in 67% (28 of 42) of breast carcinomas, 45% (5 of 11) of non-small cell lung carcinomas, 90% (9 of 10) of colon carcinomas, and 25% (3 of 12) of ovarian carcinomas. Tumors expressing a CD44 splice variant showed a significantly higher incidence of enhanced CD44 cleavage. The wide prevalence of CD44 cleavage suggests that it plays an important role in the pathogenesis of human tumors.