Abstract
The tumour microenvironment is complex and composed of many different constituents, including matricellular proteins such as connective tissue growth factor (CCN2), and is characterized by gradients in oxygen levels. In various cancers, hypoxia and CCN2 promote stem and progenitor cell properties, and regulate the proliferation, migration and phenotype of cancer cells. Our study was aimed at investigating the effects of hypoxia and CCN2 on chordoma cells, using the human U-CH1 cell line. We demonstrate that under basal conditions, U-CH1 cells express multiple CCN family members including CCN1, CCN2, CCN3 and CCN5. Culture of U-CH1 cells in either hypoxia or in the presence of recombinant CCN2 peptide promoted progenitor cell-like characteristics specific to the notochordal tissue of origin. Specifically, hypoxia induced the most robust increase in progenitor-like characteristics in U-CH1 cells, including increased expression of the notochord-associated markers T, CD24, FOXA1, ACAN and CA12, increased cell growth and tumour-sphere formation, and a decrease in the percentage of vacuolated cells present in the heterogeneous population. Interestingly, the effects of recombinant CCN2 peptide on U-CH1 cells were more pronounced under normoxia than hypoxia, promoting increased expression of CCN1, CCN2, CCN3 and CCN5, the notochord-associated markers SOX5, SOX6, T, CD24, and FOXA1 as well as increased tumour-sphere formation. Overall, this study highlights the importance of multiple factors within the tumour microenvironment and how hypoxia and CCN2 may regulate human chordoma cell behaviour.
Highlights
Chordomas are rare, malignant and locally invasive tumours that originate in bones of the skull and spine, and are thought to arise from cellular remnants of the embryonic notochord
While no change in CCN1 or CCN2 expression was detected, culture of U-CH1 cells in hypoxia promoted a significant increase in the expression of CCN3 and CCN5 compared to normoxia (Fig. 2A)
The tumour microenvironment is composed of a variety of different cell types such as cancer cells, stromal fibroblasts, endothelial cells, whose function is modulated by oxygen levels, the extracellular matrix and secreted proteins, including CCN proteins [49]
Summary
Malignant and locally invasive tumours that originate in bones of the skull and spine, and are thought to arise from cellular remnants of the embryonic notochord. Notochord cells act as tissue-specific progenitor cells that give rise to the nucleus pulposus of the intervertebral disc [3, 4]; during spine formation and notochord segmentation some of these notochord cells get trapped within the vertebral bone and are referred to as benign notochord remnants. Since these benign notochord remnants give rise to chordomas, it has been suggested that factors associated with the regulation of embryonic notochord development may likewise be associated with malignant transformation and the development of chordomas [5]. In addition to T, other transcription factors have been implicated in notochord development such as the SOX (SRY-type high mobility group box) family members SOX5, SOX6 and SOX9 [10, 11] and the forkhead box proteins A1 and A2 (FOXA1 and FOXA2) [12]
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