CD44 and its v6 spliced variant in lung tumors

Abstract

CD44 is a polymorphic family of cell surface glycoproteins with a variety of functions including participation in cell adhesion and migration as well as modulation of cell-matrix interactions. Expression of the standard form of CD44 (CD44s) and its variant isoforms has been shown in both normal and neoplastic tissue and holds promise as a prognostic indicator. The authors investigated the expression of CD44s and its v6 isoform (CD44v6) immunohistochemically in 7 fetal lungs (gestational age between 11-36 weeks) and in 80 lung tumors of various histologic types, degrees of differentiation, and clinical stages. In the fetal lung, CD44v6 was expressed as membranous and luminal staining of epithelial cells throughout gestation and basal staining of bronchial epithelium late in gestation. Nonneoplastic adult lung showed CD44v6 expression that was restricted to epithelial cells with membranous staining of basal bronchial cells and squamous metaplasia as well as basolateral membranous staining of type 2 pneumocytes. CD44s showed similar but less intense staining and was in addition present on lymphocytes and macrophages. Tumorlets and neuroepithelial bodies were CD44v6 negative. Nearly all squamous cell carcinomas (97%) were positive for CD44v6 with patterns similar to squamous metaplasia and with more intense staining at the periphery of tumor nests. Most adenocarcinomas (90%) were CD44v6 negative whereas most bronchioloalveolar cell carcinomas (71%) were CD44v6 positive with patterns similar to that in type 2 pneumocytes. Most large cell carcinomas (71%), carcinoid tumors (67%), and all small cell carcinomas were CD44v6 negative. CD44v6 expression did not correlate with clinical stage. CD44v6 expression in lymph node metastases was identical to that of the primary tumor. The results of the current study show that CD44v6 is localized differently in fetal and adult lung, suggesting a difference in function. In the fetal lung, it may modulate growth factors important in morphogenesis and maturation. In the adult nonneoplastic lung, CD44v6 is associated with stem cells, namely basal cells and type 2 pneumocytes, and may act to anchor these cells to the matrix and be important in migration during repair or neoplasia. In addition, CD44v6 expression is maintained throughout tumorigenesis in squamous cell carcinoma and bronchioloalveolar cell carcinoma, suggesting a histogenetic relationship between the stem cells and the respective tumors. Conversely, most neuroendocrine tumors and the cells of the dispersive neuroendocrine system do not express CD44v6, implying a separate histogenetic lineage in these tumors.