Bizarre giant cells in human angiosarcoma exhibit chemoresistance and contribute to poor survival outcomes.
Grace Fangmin TanShane GohAbner Herbert LimWei LiuJing Yi LeeVikneswari RajasegaranXin Xiu SamTimothy Kwang Yong TaySathiyamoorthy SelvarajanCedric Chuan-Young NgBin Tean TehJason Yongsheng ChanPublished in: Cancer science (2020)
Giant cells (GC) are a poorly understood subset of tumor cells that have been increasingly recognized as a potential contributor to tumor heterogeneity and treatment resistance. We aimed to characterize the biological and clinical significance of GC in angiosarcoma, an aggressive rare cancer of endothelial origin. Archival angiosarcoma samples were examined for the presence of GC and compared with clinicopathological as well as NanoString gene expression data. GC were examined in angiosarcoma cell lines MOLAS and ISOHAS using conventional and electron microscopy, single cell whole genome profiling, and other assays. In the cell lines, GC represented a rare population of mitotically active, non-senescent CD31+ cells, and shared similar genomic profiles with regular-sized cells, consistent with a malignant endothelial phenotype. GC remained viable and persisted in culture following exposure to paclitaxel and doxorubicin. In patient samples, GC were present in 24 of 58 (41.4%) cases. GC was correlated with poorer responses to chemotherapy (25.0% vs 73.3%, P = 0.0213) and independently contributed to worse overall survival outcomes (hazard ratio 2.20, 95% confidence interval 1.17-4.15, P = 0.0142). NanoString profiling revealed overexpression of genes, including COL11A1, STC1, and ERO1A, accompanied by upregulation of immune-related metabolic stress and metastasis/matrix remodeling pathways in GC-containing tumors. In conclusion, GC may contribute to chemoresistance and poor prognosis in angiosarcoma.
Keyphrases
- induced apoptosis
- single cell
- poor prognosis
- gas chromatography
- cell cycle arrest
- gene expression
- endothelial cells
- rna seq
- cell proliferation
- drug delivery
- signaling pathway
- oxidative stress
- dna methylation
- cell death
- high throughput
- genome wide
- squamous cell carcinoma
- case report
- high resolution
- machine learning
- tandem mass spectrometry
- climate change
- copy number
- smoking cessation
- locally advanced
- lymph node metastasis
- cancer therapy
- stress induced