Matrix Gene Expression Analysis and Cellular Phenotyping in Chordoma Reveals Focal Differentiation Pattern of Neoplastic Cells Mimicking Nucleus Pulposus Development

Abstract

Chordoma is the fourth most common malignant primary neoplasm of the skeleton and almost the only one showing a real epithelial phenotype. Besides classic chordoma, so-called chondroid chordoma was described as a specific entity showing cartilage-like tissue within chordomatoid structures. However, since its first description, strongly conflicting results have been reported about the existence of chondroid chordoma and several studies suggested chondroid chordomas being in fact low-grade conventional chondrosarcomas. In the present study, we used cytoprotein expression profiling and molecular in situ localization techniques of marker gene products indicative of developmental phenotypes of chondrocytes to elucidate origin and biology of chondroid chordoma. We were able to demonstrate the chondrogenic potential of chordomas irrespectively of the appearance of overt cartilage formation by identifying the multifocal expression of type II collagen, the main marker of chondrocytic differentiation. Additionally, the cartilage-typical large aggregating proteoglycan aggrecan was present throughout all chordomas and, thus, a very characteristic gene product and marker of these neoplasms. Biochemical matrix composition and cell differentiation pattern analysis showed a high resemblance of classic chordomas and in chordoid areas of chondroid chordomas to the fetal chorda dorsalis, whereas chondroid areas of chondroid chordomas showed features similar to adult nucleus pulposus. This demonstrates on the cell function level the chon-

Metaplasia, intraepithelial neoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis

“…Our study extends previous observations about relevant analogies between tumorigenesis and normal tissue development [1,18,22]. It suggests that a decisive step for gastric carcinogenesis is dedifferentiation, defining a backward change of differentiated epithelial cells into a fetal-like phenotype.…”

Extraskeletal myxoid chondrosarcomas do not show a chondrocytic phenotype

“…9,10 Chordomas show even stronger aggrecan positivity than extraskeletal myxoid chondrosarcomas and in many cases positivity for cartilage collagen type II even in the absence of ouvert cartilage formation. 44 Chordomas are also strongly positive for S-100 and epithelial cytokeratins and EMA throughout the lesion. The matrix gene pattern in extraskeletal myxoid chondrosarcomas distinguishes them from soft-tissue chondromas.…”

Identification of novel nucleus pulposus markers

“…GPC3, KRT19 and PTN are all involved in tissue development and differentiation, with KRT19 in particular being expressed by the human embryonic notochord 90 and chordoma. 91 Interestingly, KRT19 expression in the rat NP is not restricted to the notochordal cell-rich NP and has also been found in adult (two-year-old) rat NP, where large vacuolated notochordal cells were reported to be absent. 80 …”