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Biological Effects of Intraoperative Radiation Therapy (IORT): Histopathological Changes and Immunomodulation in Breast Cancer Patients

ABSTRACT: Intraoperative radiation therapy (IORT) delivers a single accelerated radiation dose directly to the breast tumor bed. The synergistic effects of simultaneous surgery and radiation are poorly understood. We here explored the cellular and molecular changes induced by IORT in the tumor bed compared to no-IORT exposed breast tissues. Squamous metaplasia (SM) was identified in both cohorts; however, squamous metaplasia with atypia (SMwA) was only seen in IORT specimens (63.6%, p=0.004). SMwA mimicked DCIS on histology, requiring confirmatory stains (i.e., estrogen receptor and p63) for diagnosis. Neither SM nor SMwA were found in the initial BCS specimen. We identified 1,662 differentially expressed genes (875 upregulated and 787 downregulated) between IORT and non-IORT samples. Gene ontology analyses showed that IORT was associated with the enrichment of several immune response pathways, such as inflammatory response, granulocyte activation, and T-cell activation (p<0.001). Notably, when only considering normal tissue from both cohorts, IORT was associated with intrinsic apoptotic signaling (p<0.001). Finally, we inferred a higher abundance of gamma delta T-cells, dendritic cells, and monocytes in the IORT samples compared to non-IORT samples. In conclusion, IORT induces histological changes, including squamous metaplasia with atypia, and elicits molecular alterations associated with intrinsic apoptotic signaling and immune response pathways. The higher abundance of immune-related components in breast tissue exposed to IORT suggests a potential shift towards active immunogenicity in traditionally considered immune-desert tumors such as HR-positive/HER2-negative breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253650 | GEO | 2024/04/14

REPOSITORIES: GEO

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Project description:Barrett's esophagus is characterized by the replacement of squamous epithelium with specialized intestinal metaplastic mucosa. The exact mechanisms of initiation and development of Barrett's metaplasia remain unknown, but a hypothesis of successful adaptation against noxious reflux components has been proposed. To search for the repertoire of adaptation mechanisms of Barrett's metaplasia, we employed high-throughput functional genomic and proteomic methods that defined the molecular background of metaplastic mucosa resistance to reflux. Transcriptional profiling was established for 23 pairs of esophageal squamous epithelium and Barrett's metaplasia tissue samples using Affymetrix U133A 2.0 GeneChips and validated by quantitative real-time polymerase chain reaction. Differences in protein composition were assessed by electrophoretic and mass-spectrometry-based methods. Among 2,822 genes differentially expressed between Barrett's metaplasia and squamous epithelium, we observed significantly overexpressed metaplastic mucosa genes that encode cytokines and growth factors, constituents of extracellular matrix, basement membrane and tight junctions, and proteins involved in prostaglandin and phosphoinositol metabolism, nitric oxide production, and bioenergetics. Their expression likely reflects defense and repair responses of metaplastic mucosa, whereas overexpression of genes encoding heat shock proteins and several protein kinases in squamous epithelium may reflect lower resistance of normal esophageal epithelium than Barrett's metaplasia to reflux components. Despite the methodological and interpretative difficulties in data analyses discussed in this paper, our studies confirm that Barrett's metaplasia may be regarded as a specific microevolution allowing for accumulation of mucosal morphological and physiological changes that better protect against reflux injury. Department of Gastroenterology, Medical Center for Postgraduate Education and Maria SkM-EM-^Bodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland 2 types of tissue sample derived from the same patient: > Normal squamous epithelium (NE) from patients with longsegment of BarretM-bM-^@M-^Ys epithelium > Metaplastic epithelium from BarrettM-bM-^@M-^Ys esophagus (BE)

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Biological Effects of Intraoperative Radiation Therapy (IORT): Histopathological Changes and Immunomodulation in Breast Cancer Patients

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