IntroductionThe immune system plays a major role in cancer progression. In solid tumors, 5-40 % of the tumor mass consists of tumor-associated macrophages (TAMs) and there is usually a correlation between the number of TAMs and poor prognosis, depending on the tumor type. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive, contribute to the matrix-remodeling, and hence favor tumor growth. The role of TAMs is not fully understood in breast cancer progression.MethodsMacrophage infiltration (CD68) and activation status (HLA-DRIIα, CD163) were evaluated in a large cohort of human primary breast tumors (562 tissue microarray samples), by immunohistochemistry and scored by automated image analysis algorithms. Survival between groups was compared using the Kaplan-Meier life-table method and a Cox multivariate proportional hazards model. Macrophage education by breast cancer cells was assessed by ex vivo differentiation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of breast cancer cell conditioned media (MDA-MB231, MCF-7 or T47D cell lines) and M1 or M2 inducing cytokines (respectively IFN-γ, IL-4 and IL-10). Obtained macrophages were analyzed by flow cytometry (CD14, CD16, CD64, CD86, CD200R and CD163), ELISA (IL-6, IL-8, IL-10, monocyte colony stimulating factor M-CSF) and zymography (matrix metalloproteinase 9, MMP-9).ResultsClinically, we found that high numbers of CD163+ M2-macrophages were strongly associated with fast proliferation, poor differentiation, estrogen receptor negativity and histological ductal type (p<0.001) in the studied cohort of human primary breast tumors. We demonstrated ex vivo that breast cancer cell-secreted factors modulate macrophage differentiation toward the M2 phenotype. Furthermore, the more aggressive mesenchymal-like cell line MDA-MB231, which secretes high levels of M-CSF, skews macrophages toward the more immunosuppressive M2c subtype.ConclusionsThis study demonstrates that human breast cancer cells influence macrophage differentiation and that TAM differentiation status correlates with recurrence free survival, thus further emphasizing that TAMs can similarly affect therapy efficacy and patient outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0621-0) contains supplementary material, which is available to authorized users.
Published descriptions of the neuropathological features of COVID-19 patients have been controversial, ranging from only modest or no pathology to severe hypoxic and hemorrhagic phenotypes, thrombotic complications, acute disseminated encephalomyelitis-like changes, and encephalitis and meningitis. Here, we describe the neuropathological findings of four COVID-19-positive patients autopsied at the Helsinki University Hospital during the spring of 2020. While three of the patients (age range 63-90) exhibited merely mild to moderate hypoxia-associated changes, one 38-year-old subject with obesity, diabetes (type 2), Parkinson's disease and a very severe clinical course was found to have severe ischemic injury, abundant microhemorrhages and enlarged perivascular spaces most pronounced in the white matter and deep gray matter. The pattern of ischemic changes suggested a defect in microcirculation. In addition, a few small perivascular white matter lesions, with macrophages engulfing myelin, were found. No signs of encephalitis or meningitis were detected in any of the patients. When conducting RT-PCR and immunohistochemical analyses of brain tissue, we could not demonstrate in any of the patients marked injury or presence of SARS-CoV2 in the olfactory epithelium, olfactory bulbs or brain areas responsible for respiratory control. In conclusion, our small autopsy series demonstrates various hypoxia-associated neuropathological features in COV-ID-19 patients, but no evidence of neurotropism or meningitis/encephalitis.
Despite frequent KIT protein expression in some tumor types, KIT and PDGFRA gene mutations are uncommon in most human cancers. Cancer KIT expression is frequently associated with multiple copies of the wild-type KIT gene.
Receptor tyrosine kinase aberrations are implicated in the genesis of gliomas. We investigated expression and amplification of KIT, PDGFRA, VEGFR2, and EGFR in 87 gliomas consisting of astrocytomas, anaplastic astrocytomas, oligodendrogliomas, or oligoastrocytomas in tumor samples collected at the time of the diagnosis and in samples of the same tumors at tumor recurrence. Gene amplifications were investigated using either chromogenic in situ hybridization or fluorescence in situ hybridization, and protein expression using immunohistochemistry. In samples collected at glioma diagnosis, KIT and PDGFRA amplifications were more frequent in anaplastic astrocytomas than in astrocytomas, oligodendrogliomas, and oligoastrocytomas [28% versus 5% (P = 0.012) and 33% versus 2% (P = 0.0008), respectively]. VEGFR2 amplifications occurred in 6% to 17% of the gliomas at diagnosis, and EGFR amplifications in 0% to 12%. Amplified KIT was more frequently present in recurrent gliomas than in newly diagnosed gliomas (P = 0.0066). KIT amplification was associated with KIT protein expression and with presence of PDGFRA and EGFR amplifications both at the time of the first glioma diagnosis and at tumor recurrence, and with VEGFR2 amplification at tumor recurrence. Three (4%) primary gliomas and 10 (14%) recurrent gliomas that were evaluable for coamplification of KIT, PDGFRA, and VEGFR2 showed amplification of at least two of these genes; the amplicon contained amplified KIT in all 13 cases. In conclusion, besides glioblastoma, amplified KIT, PDGFRA, and VEGFR may also occur in lower-grade gliomas and in their recurrent tumors. It is currently not known whether specific tyrosine kinase inhibitors are effective in the treatment of such gliomas.
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