The role of mesenchymal stem cells in bone cancer: initiation, propagation, and metastasis

Introduction to the mesenchymal stem cell

Multipotent stem cells are of great interest in biomedical research, since they have the potential to produce all kinds of tissues that can be used to repair damaged organs. In a time when human life span is extended, the opportunity to replace body parts that have become dysfunctional as a result of aging or because of surgery, vascular failure, or inflammation is a blessing, especially when donor cells can be obtained from the patient itself, thereby preventing unwanted immunological rejection.

Mesenchymal stem cells (MSCs) are the most promising pharmaceutical multipotent cells, although their beneficiary effect is overestimated by clinics that pledge miraculous healing of all kinds of incurable diseases, even recently MSCs are put forward as a therapeutic for COVID-19 patients [ ]. Confusion about the merits of MSC treatment is still an ongoing subject of debate [ ].

MSCs, also designated mesenchymal stromal cells or mesenchymal precursor cells, are undifferentiated self-renewing precursor cells that can differentiate into bone, cartilage, adipose tissue, and connective stromal cells. Other cell types such as neural-, epithelial-, and muscle cells have been suggested as well to arise from MSCs, but this is mainly observed in vitro under particular culture conditions [ , ]. The number of clinical trials using MSCs is near 1000 and includes trials for immunomodulation, multiple sclerosis, regenerative medicine, tissue protection, and graft enhancement [ ]. The cells are popular biopharmaceuticals since they are easy to harvest from bone marrow, together with the hematopoietic stem cells, from which they are distinguished by their propensity to adhere to the plastic culture dish as well as a number of surface markers (CD73, CD90, and CD105), of which none is actually entirely specific for MSCs. Subsequently the MSC culture can be expanded in vitro resulting in sufficient material to treat the patient from which these cells were originally derived. MSCs can furthermore be obtained from adipose tissue and cord blood.

However, apart from their beneficial role in medical practice there is a dark side to the MSC, which asks for caution in the application of these cells as biopharmaceutical [ , ]. The most discomforting property is that MSCs are most probably the progenitors of sarcomas and even worse that MSCs cultured in vitro can transform and give rise to tumors upon grafting [ ]. This will be discussed in the following paragraph. This observation can be extrapolated to the cancer stem cell (CSC) theory, which may explain why initially therapy-responding tumors become resistant as a result of obscure remaining cells that have stemlike properties and give rise to recurrences and metastases. Another unsettling concept attributed to the MSC is their possible role in metastasis. Already in 1889 it was suggested that for metastases the soil had to be prepared for seeding the tumor cells [ ] and a role for MSCs in this process has been proposed. Furthermore the MSCs provide the niche for primary bone tumors and can be considered as cancer-associated cells, just like the CAFs (cancer-associated fibroblasts) described in epithelial tumors. A more general role of MSCs in the tumor microenvironment was recently reviewed [ ]. This chapter focuses on the role of MSCs in initiation, propagation, and metastasis of bone tumors.

Initiation: MSCs as progenitors of bone tumors

The sudden, early onset in highly malignant osteosarcoma and Ewing sarcoma suggests a unique mechanism in carcinogenesis. The lack of a benign precursor for these devastating tumors in young patients is curious and not in line with the multistep tumor evolution model as formulated by Bert Vogelstein [ ]. This model was designed for epithelial tumors that arise at late age and are characterized by a slow development of malignant clones during multiple cell divisions. Malignant mesenchymal bone tumors most probably have a more abrupt mechanism of development reflected by their specific somatic genetic makeup, i.e., chromothripsis, where chromosomes seem to be scrambled and stitched incorrectly in a single event [ ] and the pathognomonic translocations in Ewing sarcoma. Apart from the mechanism of bone sarcoma genesis there is the issue of the MSC as the progenitor cell of bone sarcoma.

This paragraph presents the different bone tumor types and which observations point to the MSC as progenitor cell [ ]. But first as a general topic: the propensity of MSCs to degenerate into malignant cells. This has been repeatedly observed in MSCs isolated from laboratory mice's bone marrow [ ]. The MSCs become highly aneuploid after more or less passages and produce sarcomatous malignancies upon transplantation in mice or show migration in zebrafish embryos [ ]. Of course this is quite unsettling for MSC clinical practice. Fortunately this transformation was not observed in human MSCs even after long-term culturing [ ] ( Figure 12.1 ). One report suggested that this malignant transformation could also occur in MSCs from human origin [ ], but this was later refuted by a publication that it was due to a contamination with the highly malignant human sarcoma cell line HT1080 [ ].

Chondrogenic tumors

In general chondrogenic tumors arise at late age and are less aggressive than osteosarcoma and Ewing sarcoma. Most benign chondrogenic lesions, enchondromas and osteochondromas, never develop into malignancy and only 1%–5% deteriorate to chondrosarcoma [ ]. The development of osteochondromas is definitely confined to young age, since they can only expand when the growth plate at the epiphysis of long bones is still open. At the end of puberty the growth plate closes and the osteochondroma will not increase [ ]. For the course of malignant transformation of enchondromas data are scarce [ , ] given their often symptom-free existence, but they are considered as likely precursor lesions of central chondrosarcomas.

It is debated whether central chondrosarcoma arises from a cartilage remnant from the preexistent growth plate or from an MSC. The in vivo histological and immunohistochemical features of chondrogenic tumors of different kinds and grades suggest that it represents a spectrum of various differentiation states [ ]. The analysis of extracellular gene and protein expression of tumor cells has shown the presence of mature chondrocytes as well as cells resembling hypertrophic chondrocytes or chondrocytes at an earlier stage of differentiation [ ]. Expression profiling of MSCs that undergo chondrogenic differentiation identified a profile that resembles quite well the genes that are also expressed by chondrosarcoma, and a distinction can be made between low-grade chondrosarcoma, characterized by a prechondrogenic expression profile versus high-grade chondrosarcoma with a typical profile of terminally differentiated cartilage genes [ ]. This suggests MSCs as likely progenitors of chondrogenic tumors. However, little experimental data are available that can support the presumed MSC progenitor theory for chondrogenic tumors. Nevertheless the different types of chondrogenic tumors certainly recapitulate the stages of differentiation of MSCs toward chondrocytes. This is nicely depicted in Figure 12.2 , which is a copy of the model proposed by Thomas Aigner and shows the analogy of the differentiation stage of the MSC and the various types and stages of chondrogenic tumors [ ]. Indeed, gene expression profiling of MSCs and their chondrogenic derivatives shows that chondrosarcomas with different differentiation grades states show parallels with MSC maturation along the chondrogenic pathway [ ]. The mutation in the gene encoding isocitrate dehydrogenase (IDH) which is frequently found in enchondromas as well as chondrosarcomas was shown to promote chondrogenic and suppress osteoblastic differentiation in MSCs [ , ].