ABSTRACT
Triple-negative (TN) breast cancers (ER-PR-HER2-) are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance.
Subject(s)
Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Chemokine CXCL16/metabolism , Chemotactic Factors/pharmacology , Monocytes/pathology , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Animals , Cancer-Associated Fibroblasts/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Coculture Techniques , Collagen/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Immunosuppression Therapy , Mice, Nude , Monocytes/drug effects , Monocytes/metabolism , Myeloid Cells/metabolism , Myeloid Cells/pathology , Solubility , Stromal Cells/pathology , Triple Negative Breast Neoplasms/genetics , Tumor Microenvironment/drug effects , Xenograft Model Antitumor AssaysABSTRACT
UNLABELLED: In daily practice mycotic infections of the CNS have become more and more frequent. The main causes are the wide-ranging use of corticosteroids, immunosuppressive, cytostatic drugs and antibiotics, the spreading of AIDS, the increasing number of surviving immature newborns. To illustrate the diagnostic difficulties, the authors report several cases. CASE REPORTS: 1. Multifocal hemorrhagic infarcts of the brain, caused by generalized aspergillosis in mantle cell malignant lymphoma. 2. Cerebral microabscesses, caused by systemic candidiasis in a premature infant. 3. Fatal actinomycosis, mimicking a space occupying tumour in the thigh and with an abscess in the brain, radiologically indicated as a metastasis. The cause of death was actinomycotic pneumonia. 4. A successfully treated and recovered patient with recurrent pneumonia and multiplex brain abscesses, caused by filamentous microorganism of a Nocardia species revealed by histological examination of the neurosurgical specimen. DISCUSSION AND CONCLUSIONS: We have to be aware for the development of the mycotic and related infections of endangered patients. Aspergillosis and candidiasis play the most significant role in the involvement of the central nervous system. Actinomycosis and nocardiosis are more sensitive to treatment, so their diagnosis is of life-saving importance. The therapeutic chances of high risk patients with aspergillosis and candidiasis will be definitively better, if the infection is recognized and appropriately treated before the involvement of the CNS.
