18 research outputs found
Hodgkin Lymphoma: A Special Microenvironment
Classical Hodgkin’s lymphoma (cHL) is one of the most particular lymphomas for the few tumor cells surrounded by an inflammatory microenvironment. Reed-Sternberg (RS) and Hodgkin (H) cells reprogram and evade antitumor mechanisms of the normal cells present in the microenvironment. The cells of microenvironment are essential for growth and survival of the RS/H cells and are recruited through the effect of cytokines/chemokines. We summarize recent advances in gene expression profiling (GEP) analysis applied to study microenvironment component in cHL. We also describe the main therapies that target not only the neoplastic cells but also the cellular components of the background
Interval sentinel lymph nodes in melanoma: a digital pathology analysis of Ki67 expression and microvascular density
The presence of interval sentinel lymph nodes
in melanoma is documented in several studies, but controversies
still exist about the management of these lymph
nodes. In this study, an immunohistochemical evaluation
of tumor cell proliferation and neo-angiogenesis has been
performed with the aim of establishing a correlation
between these two parameters between positive and
negative interval sentinel lymph nodes. This retrospective
study reviewed data of 23 patients diagnosed with melanoma.
Bioptic specimens of interval sentinel lymph node
were retrieved, and immunohistochemical reactions on
tissue sections were performed using Ki67 as a marker of
proliferation and CD31 as a blood vessel marker for the
study of angiogenesis. The entire stained tissue sections
for each case were digitized using Aperio Scanscope Cs
whole-slide scanning platform and stored as high-resolution
images. Image analysis was carried out on three
selected fields of equal area using IHC Nuclear and Microvessel analysis algorithms to determine positive
Ki67 nuclei and vessel number. Patients were divided into
positive and negative interval sentinel lymph node groups,
and the positive interval sentinel lymph node group was
further divided into interval positive with micrometastasis
and interval positive with macrometastasis subgroups.
The analysis revealed a significant difference between
positive and negative interval sentinel lymph nodes in the
percentage of Ki67-positive nuclei and mean vessel
number suggestive of an increased cellular proliferation
and angiogenesis in positive interval sentinel lymph
nodes. Further analysis in the interval positive lymph
node group showed a significant difference between
micro- and macrometastasis subgroups in the percentage
of Ki67-positive nuclei and mean vessel number. Percentage
of Ki67-positive nuclei was increased in the
macrometastasis subgroup, while mean vessel number
was increased in the micrometastasis subgroup. The
results of this study suggest that the correlation between
tumor cell proliferation and neo-angiogenesis in interval
sentinel lymph nodes in melanoma could be used as a
good predictive marker to distinguish interval positive
sentinel lymph nodes with micrometastasis from interval
positive lymph nodes with macrometastasis subgroups
Everolimus restrains the paracrine pro-osteoclast activity of breast cancer cells
Background: Breast cancer (BC) cells secrete soluble factors that accelerate osteoclast (OC) differentiation, leading
to the formation of osteolytic bone metastases. In the BOLERO-2 trial, BC patients with bone involvement who
received Everolimus had a delayed tumor progression in the skeleton as a result of direct OC suppression through
the inhibition of mTOR, in addition to the general suppressor effect on the cancer cells. Here, we explored the
effect of Everolimus, as mTOR inhibitor, on the pro-OC paracrine activity of BC cells.
Methods: Both MDA-MB-231 and MCF-7 BC cell lines were incubated with sub-lethal amounts of Everolimus, and
their conditioned supernatants were assessed for their capacity to differentiate OCs from PBMC from healthy
donors, as well as to interfere with their bone resorbing activity shown on calcium phosphate slices. We also
measured the mRNA levels of major pro-OC factors in Everolimus-treated BC cells and their secreted levels by
ELISA, and evaluated by immunoblotting the phosphorylation of transcription factors enrolled by pathways
cooperating with the mTOR inhibition. Finally, the in vivo pro-OC activity of these cells was assessed in SCID
mice after intra-tibial injections.
Results: We found that Everolimus significantly inhibited the differentiation of OCs and their in vitro bone-resorbing
activity, and also found decreases of both mRNA and secreted pro-OC factors such as M-CSF, IL-6, and IL-1β, whose
lower ELISA levels paralleled the defective phosphorylation of NFkB pathway effectors. Moreover, when intra-tibially
injected in SCID mice, Everolimus-treated BC cells produced smaller bone metastases than the untreated cells.
Conclusions: mTOR inhibition in BC cells leads to a suppression of their paracrine pro-OC activity by interfering
with the NFkB pathway; this effect may also account for the delayed progression of bone metastatic disease
observed in the BOLERO-2 trial.
Keywords: BOLERO-2 trial, Breast cancer cells, mTOR, Osteoclastogenesis, Everolimu
T cells, mast cells and microvascular density in diffuse large B cell lymphoma
Diffuse large B cell lymphoma (DLBCL) is recognized as the most common form of non-Hodgkin lymphoma (NHL), accounting for about 40 % of all cases of NHL. Among the cellular components of the tumor inflammatory infiltrate, T cells and mast cells have been demonstrated to be correlated with tumor angiogenesis. In this report, we have investigated CD3 and tryptase expression and their relationship with microvascular density (MVD) in DLBCL patients. Moreover, we determined the significance of CD3 expression in bulky and non-bulky disease. CD3 expression was significantly lower in bulky disease patients when compared to non-bulky ones. CD3 showed a positive correlation with tryptase and MVD, while multiple regression analysis efficaciously predicted MVD depending on CD3 and tryptase as predictors, supporting a complex interplay between these cells in sustaining tumor angiogenesis in DLBCL patients.Diffuse large B cell lymphoma (DLBCL) is recognized as the most common form of non-Hodgkin lymphoma (NHL), accounting for about 40Â % of all cases of NHL. Among the cellular components of the tumor inflammatory infiltrate, T cells and mast cells have been demonstrated to be correlated with tumor angiogenesis. In this report, we have investigated CD3 and tryptase expression and their relationship with microvascular density (MVD) in DLBCL patients. Moreover, we determined the significance of CD3 expression in bulky and non-bulky disease. CD3 expression was significantly lower in bulky disease patients when compared to non-bulky ones. CD3 showed a positive correlation with tryptase and MVD, while multiple regression analysis efficaciously predicted MVD depending on CD3 and tryptase as predictors, supporting a complex interplay between these cells in sustaining tumor angiogenesis in DLBCL patients
A New Ensemble Method for Detecting Anomalies in Gene Expression Matrices
One of the main problems in the analysis of real data is often related to the presence of anomalies. Namely, anomalous cases can both spoil the resulting analysis and contain valuable information at the same time. In both cases, the ability to detect these occurrences is very important. In the biomedical field, a correct identification of outliers could allow the development of new biological hypotheses that are not considered when looking at experimental biological data. In this work, we address the problem of detecting outliers in gene expression data, focusing on microarray analysis. We propose an ensemble approach for detecting anomalies in gene expression matrices based on the use of Hierarchical Clustering and Robust Principal Component Analysis, which allows us to derive a novel pseudo-mathematical classification of anomalies
Diffuse Large B Cell Lymphoma Arising in Patients with Preexisting Hodgkin Lymphoma
The metachronic onset of diffuse large B-cell lymphoma (DLBCL) after classic Hodgkin lymphoma (cHL) is a rare event affecting patients’ outcomes. However, although several studies have investigated the prognostic role of this event, little is known about a hypothetical common origin of the two different neoplastic cells. Aims: To investigate a possible relationship between DLBCL and cHL, in this retrospective study of 269 patients with newly diagnosed cHL treated at Bari University Hospital (Italy) between 2007 and 2020, we analyzed data from 4 patients (3 male and 1 female) with cHL who subsequently developed DLBCL. Methods: Gene expression profile analysis, assessed by NanoString Lymphoma Subtype Assay, was performed to identify the cell of origin in the DLBCL cases, in addition to Hans’s algorithm. Results: Using Hans’s algorithm, all DLBCL cases showed a germinal center-B-Cell subtype. The gene expression profile evaluated by the NanoString Lymphoma Subtype Assay revealed two cases of the GCB molecular subtype, while the others were unclassified. After first-line chemotherapy, 1 patient achieved complete remission, 3 were non-responders (2 died of lymphoma within 6 months, whereas the other achieved complete remission after autologous and allogeneic stem cell transplantation and is still alive). Conclusions: The origin of the second neoplastic cell in patients with DLBCL with a previous history of cHL remains controversial, although the different immunophenotypic characteristics suggest that it may mainly arise de novo in a subject with a possible individual predisposition to develop lymphoid neoplasms
The Effect of the Tumor Microenvironment on Lymphoid Neoplasms Derived from B Cells
Lymphomas are characteristic tumors surrounded by an inflammatory microenvironment. The cells of the microenvironment are essential for the growth and survival of neoplastic cells and are recruited through the effect of cytokines/chemokines. Lymphomas include heterogeneous groups of neoplasms infiltrating various lymphoid structures which may arise from B lymphocytes, T lymphocytes, and natural killer (NK) cells at various stages of their differentiation state. In this review article, we analyze the literature data concerning the involvement of the tumor microenvironment (TME) in the progression of lymphomas and the recent advances in the analysis of microenvironment components in the most common forms: some mature B cell lymphoma neoplasms and classic Hodgkin lymphomas. The complex crosstalk between the TME and tumor cells led to the discovery of many mechanisms usable as molecular-targeted therapy through the control of diverse elements of the TME, varying from inhibitors of angiogenic cytokines and their receptors to the regulation of cells’ activities and the novel immune checkpoint inhibitors
Additional file 1: Figure S1. of Everolimus restrains the paracrine pro-osteoclast activity of breast cancer cells
Measurement of Everolimus cytotoxicity on BC cell lines. Table S1. Primer sequences used for Real-Time PCR. Table S2. Optical density (OD) values, normalized to ĂŽË›-actin, by Western blot analyses. (DOCX 78 kb