ABSTRACT
Intratumoral heterogeneity (ITH) represents an obstacle for cancer diagnosis and treatment, but little is known about its functional role in cancer progression. The A Desintegrin And Metalloproteinase 23 (ADAM23) gene is epigenetically silenced in different types of tumors, and silencing is often associated with advanced disease and metastasis. Here, we show that invasive breast tumors exhibit significant ADAM23-ITH and that this heterogeneity is critical for tumor growth and metastasis. We demonstrate that while loss of ADAM23 expression enhances invasion, it causes a severe proliferative deficiency and is not itself sufficient to trigger metastasis. Rather, we observed that, in ADAM23-heterotypic environments, ADAM23-negative cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent A23-positive cells through the production of LGI4 (Leucine-rich Glioma Inactivated 4) and nitric oxide (NO). Ablation of LGI4 and NO in A23-negative cells significantly attenuates A23-positive cell proliferation and invasion. Our work denotes a driving role of ADAM23-ITH during disease progression, shifting the malignant phenotype from the cellular to the tissue level. Our findings also provide insights for therapeutic intervention, enforcing the need to ascertain ITH to improve cancer diagnosis and therapy.
Subject(s)
ADAM Proteins/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Extracellular Matrix Proteins/metabolism , Nitric Oxide/metabolism , ADAM Proteins/genetics , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation , DNA Methylation , Epigenesis, Genetic , Extracellular Matrix Proteins/genetics , Female , Gene Silencing , Humans , Neoplasm Metastasis , Nerve Tissue Proteins , Tumor Burden , Tumor MicroenvironmentSubject(s)
Fetal Diseases/pathology , Vaccinia/pathology , Adolescent , Female , Humans , Pregnancy , Skin/pathology , Vaccinia virus/isolation & purificationABSTRACT
A case in which, besides the clinical complications that commonly follow snake biting, abruptio placentae occurred is reported here. None of the factors that are frequently associated with abruptio placentae were present. The laboratory tests performed showed that renal function was impaired and that a dramatic hypercoagulability was present. The relationship of the latter to the abruptio placentae is discussed.
