Bizarre giant cells in human angiosarcoma exhibit chemoresistance and confer poor survival outcomes.

Giant cells (GCs) are a poorly understood subset of tumor cells increasingly recognized as a potential contributor to tumor heterogeneity and treatment resistance. We aim to characterize the biological and clinical significance of GCs in angiosarcoma - an aggressive rare cancer of endothelial origin. Archival angiosarcoma samples were examined for the presence of GCs and correlated with clinicopathological as well as NanoString gene expression data. GCs in angiosarcoma cell lines MOLAS and ISOHAS were examined via conventional and electron microscopy, single cell whole genome profiling and other assays. In the cell lines, GCs were 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. GCs remained viable and persisted in culture following exposure to paclitaxel and doxorubicin. In patient samples, GCs were present in 24 of 58 (41.4%) cases, correlated with poorer responses to chemotherapy (25.0% vs 73.3%, p = 0.0213), and independently conferred worse overall survival outcomes (HR 2.20, 95% CI 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, GCs may confer chemoresistance and poor prognosis in angiosarcoma.