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Biology of cartilage tumor family


Research highlights

  • The cartilage tumor family is a heterogeneous group of tumors, driven by mutations, translocations, or unknown factors.

  • The biology of cartilage tumors is reflected by defective growth plate signaling pathways.

  • Chondrosarcomas can arise within a benign precursor or arise de novo.

  • Some benign cartilage tumors (enchondroma and osteochondroma) are composed of a mixture of mutant and wild-type cells.

  • Molecular alterations used in diagnostics include IDH or H3F3B K36M mutations, and HEY-NCOA2 fusion.

Introduction

The group of cartilage tumors encompasses benign, intermediate, as well as malignant entities, all of which show at least to some extent biological mechanisms reminiscent of normal epiphyseal growth plate development. For many of them the underlying molecular events have been identified, although the mechanism by which these alterations disturb the normal mesenchymal differentiation is known for only a subset.

Normal growth plate development

The normal epiphyseal growth plate consists of an organized proliferation and differentiation of chondrocytes. These cells start in the resting zone, subsequently proliferate, and transition toward prehypertrophic and hypertrophic chondrocytes. Eventually, they undergo apoptosis which results in mineralization of the matrix surrounding the apoptotic chondrocytes as well as vessel invasion, bringing in osteoblasts that start the formation of bone. Eventually, this process of enchondral ossification thus leads to growth of long bones [ ]. Interestingly, there is recent evidence that some of the terminally differentiated hypertrophic chondrocytes survive and undergo phenotypical transformation to osteoblast-like cells [ , ], thereby contributing to the ossification and growth process.

The process of enchondral ossification is tightly regulated by the Indian hedgehog (IHH)-parathyroid hormone–like hormone (PTHLH) pathway, which forms a negative feedback loop ( Fig. 45.1 ) [ ]. Prehypertrophic and hypertrophic chondrocytes secrete the growth factor IHH, which then diffuses away and induces increase of the proliferation rate of proliferating chondrocytes [ , ]. In addition, IHH acts as a long range signaling molecule by stimulating the secretion of PTHLH by perichondrial cells. This inhibits chondrocyte differentiation and expression of IHH by upregulation of the antiapoptotic protein Bcl-2, thereby keeping chondrocytes in a proliferating state. Hypertrophic differentiation of chondrocytes and enchondral ossification start when PTHLH levels drop below a certain threshold [ , ]. Enchondromas, osteochondromas, and chondrosarcomas are associated with deregulation of this IHH-PTHLH pathway [ , ].

Figure 45.1, Normal growth plate signaling.

Extracellular matrix of articular cartilage

Biochemical studies have shown that the composition of the extracellular tumor matrix of enchondromas and chondrosarcomas is similar to fetal and adult cartilage [ , ]. Nonetheless, there are significant differences in the quantity of various matrix proteins such as collagens and proteoglycans [ ].

The extracellular matrix of articular cartilage is mainly composed of type II collagen and mutations in COL2A1 have been found in chondrosarcomas, while it is also involved in cartilage degeneration in osteoarthritis and in chondrodysplasia [ ]. COL2A1 encodes the α-chain of type II collagen fibers and mutations in COL2A1 result in aberrant procollagen α-chain [ ].

Benign cartilage tumors

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