ABSTRACT
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.
Subject(s)
Breast Implants , Breast Neoplasms , Lymphoma, Large-Cell, Anaplastic , Animals , Breast Implants/adverse effects , Female , Humans , Hypoxia/genetics , Immunohistochemistry , Lymphoma, Large-Cell, Anaplastic/genetics , Mice , Tumor MicroenvironmentSubject(s)
Gastrointestinal Neoplasms/complications , Janus Kinase 2/antagonists & inhibitors , Lymphoma, T-Cell/drug therapy , Lymphoproliferative Disorders/drug therapy , Pyrazoles/pharmacology , STAT3 Transcription Factor/antagonists & inhibitors , T-Lymphocytes/drug effects , Animals , Apoptosis , Cell Proliferation , Humans , Lymphoma, T-Cell/metabolism , Lymphoma, T-Cell/pathology , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/metabolism , Lymphoproliferative Disorders/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Nitriles , Oncogene Proteins, Fusion/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The dental professions hold an important responsibility in the control of oral cancer and the early diagnosis highly depends on their knowledge. The present study was developed to assess the knowledge, attitude, and practice of dentists in Khartoum State regarding oral cancer prevention and early detection. An administered questionnaire was structured and sent to all licensed 130 dentists working in public dental clinics in Khartoum State. Responses to the questionnaire were analyzed using descriptive and analytical statistics. Although the majority of the dentists were knowledgeable about the major risk factors of oral cancer, more than half of the dentists reported they do not carry out any special examination to detect oral cancer in age 40 and above in asymptomatic patients. Dentists indicated their lack of training as the main barrier for conducting a comprehensive oral cancer examination. Interestingly, the vast majority of the dentists express their interest to have further oral cancer educational and training sessions. The findings of the present study suggested strongly that educational and training interventions are necessary to enhance preventive measures which may lead to reduce mortality and morbidity from oral cancer.
