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1.
Surgery ; 174(2): 277-282, 2023 08.
Article in English | MEDLINE | ID: mdl-37263880

ABSTRACT

BACKGROUND: Resection of metastatic hepatic tumors of breast cancer may result in the acceleration of hepatic and extrahepatic tumor progression due to the microenvironmental circulation of chemokines. This study aimed to investigate the effect of hepatectomy on a large panel of chemokines, liver regeneration, and myeloid cell levels in an experimental breast cancer model. METHODS: The 4T1 breast cancer cells were inoculated, and 30% to 40% hepatectomy was performed. Mice without tumors or only laparotomy (no hepatectomy) served as control groups. After 14 days (short-term) and 21 days (long-term), tissue samples were obtained from the regions near and distant from the resection site. Chemokine levels were evaluated by enzyme-linked immunosorbent assay arrays. Myeloid infiltration in the liver and the primary tumor and hepatic regeneration status were also histopathologically evaluated. RESULTS: The levels of pro-tumorigenic chemokines such as CCL2, CCL3, CCL4, and CCL5 were elevated in hepatectomized tumor-bearing animals. This observation was consistent with the presence of hepatic metastases. Liver regeneration and myeloid cell infiltration showed significant differences between the tumor-bearing hepatectomized groups followed in the short and long term. CONCLUSION: Our study showed elevation and variations in chemokines after hepatectomy, with a prominent increase in pro-tumorigenic chemokines. These results can be associated with the acceleration of metastasis after liver resection. However, further prospective studies are required to better define the impact of resection, which may transform the liver into a favorable site for metastasis.


Subject(s)
Hepatectomy , Liver Neoplasms , Mice , Animals , Chemokines , Liver Neoplasms/surgery , Liver Neoplasms/secondary , Liver Regeneration
2.
Cancer Immunol Immunother ; 71(2): 445-459, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34228218

ABSTRACT

Small cell lung cancer (SCLC) is an aggressive tumor type with early dissemination and distant metastasis capacity. Even though optimal chemotherapy responses are observed initially in many patients, therapy resistance is almost inevitable. Accordingly, SCLC has been regarded as an archetype for cancer stem cell (CSC) dynamics. To determine the immune-modulatory influence of CSC in SCLC, this study focused on the characterization of CD44+CD90+ CSC-like subpopulations in SCLC. These cells displayed mesenchymal properties, differentiated into different lineages and further contributed to CD8+ cytotoxic T lymphocytes (CTL) responses. The interaction between CD44+CD90+ CSC-like cells and T cells led to the upregulation of checkpoint molecules PD-1, CTLA-4, TIM-3, and LAG3. In the patient-derived lymph nodes, CD44+ SCLC metastases were also observed with T cells expressing PD-1, TIM-3, or LAG3. Proliferation and IFN-γ expression capacity of TIM-3 and LAG3 co-expressing CTLs are adversely affected over long-time co-culture with CD44+CD90+ CSC-like cells. Moreover, especially through IFN-γ secreted by the T cells, the CSC-like SCLC cells highly expressed PD-L1 and PD-L2. Upon a second encounter with immune-experienced, IFN-γ-stimulated CSC-like SCLC cells, both cytotoxic and proliferation capacities of T cells were hampered. In conclusion, our data provide evidence for the superior potential of the SCLC cells with stem-like and mesenchymal properties to gain immune regulatory capacities and cope with cytotoxic T cell responses. With their high metastatic and immune-modulatory assets, the CSC subpopulation in SCLC may serve as a preferential target for checkpoint blockade immunotherapy .


Subject(s)
B7-H1 Antigen/metabolism , Lung Neoplasms/pathology , Mesenchymal Stem Cells/pathology , Neoplastic Stem Cells/pathology , Programmed Cell Death 1 Ligand 2 Protein/metabolism , Small Cell Lung Carcinoma/pathology , T-Lymphocytes, Cytotoxic/immunology , Apoptosis , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Humans , Hyaluronan Receptors/metabolism , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Mesenchymal Stem Cells/immunology , Mesenchymal Stem Cells/metabolism , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , Small Cell Lung Carcinoma/immunology , Small Cell Lung Carcinoma/metabolism , Tumor Cells, Cultured
3.
Front Physiol ; 12: 679919, 2021.
Article in English | MEDLINE | ID: mdl-34177624

ABSTRACT

Diamond Blackfan Anemia (DBA) is an inherited bone marrow (BM) failure syndrome, characterized by a paucity of erythroid differentiation. DBA is mainly caused by the mutations in ribosomal protein genes, hence classified as ribosomopathy. However, in approximately 30% of patients, the molecular etiology cannot be discovered. RPS19 germline mutations caused 25% of the cases. On the other hand, CECR1 mutations also cause phenotypes similar to DBA but not being a ribosomopathy. Due to the blockade of erythropoiesis in the BM, we investigated the transcriptomic profile of three different cell types of BM resident cells of DBA patients and compared them with healthy donors. From BM aspirates BM mononuclear cells (MNCs) were isolated and hematopoietic stem cells (HSC) [CD71-CD34+ CD38mo/lo], megakaryocyte-erythroid progenitor cells (MEP) [CD71-CD34+ CD38hi] and Proerythroblasts [CD71+ CD117+ CD38+] were sorted and analyzed with a transcriptomic approach. Among all these cells, proerythroblasts had the most different transcriptomic profile. The genes associated with cellular stress/immune responses were increased and some of the transcription factors that play a role in erythroid differentiation had altered expression in DBA proerythroblasts. We also showed that gene expression levels of ribosomal proteins were decreased in DBA proerythroblasts. In addition to these, colony formation assay (CFU-E) provided functional evidence of the failure of erythroid differentiation in DBA patients. According to our findings that all patients resembling both RPS19 and CECR1 mutations have common transcriptomic signatures, it may be possible that inflammatory BM niche may have a role in DBA pathogenesis.

4.
Mol Pharm ; 15(4): 1526-1533, 2018 04 02.
Article in English | MEDLINE | ID: mdl-29481086

ABSTRACT

While reshaping their microenvironment, tumors are also capable of influencing systemic processes including myeloid cell production. Therefore, the tumor-induced myeloid cells, such as myeloid-derived suppressor cells (MDSCs), which are characterized with pro-cancer properties, became another target in order to increase the success of the therapy. This study evaluated the capacity of a novel dendrimeric drug delivery platform to eliminate tumor-induced myeloid cells. As described in a previous study by our research group, the anti-Flt1 antibody-conjugated polyethylene glycol (PEG)-cored poly(amidoamine) (PAMAM) dendrimers improved the efficacy of gemcitabine against pancreatic cancer. Here, the biodistribution studies showed that these dendrimeric structures accumulated in the compartments that became rich in myeloid cells in the pancreatic tumor-bearing mice. When gemcitabine was loaded into the dendrimer complexes, the number of myeloid cells was significantly reduced while the percentage distribution of granulocytic and monocytic myeloid cells was not always significantly altered. The CD11b+Ly6G-Ly6C+ monocytes were more severely affected by the treatments than CD11b+Ly6G+Ly6C+ granulocytes. Immune infiltration levels in the tumor tissue were also altered. Myeloid cells in the spleen and F4/80+ macrophages of the liver were protected. The compartments, such as the liver and the bone marrow, which are known to have high vascular endothelial growth factor (VEGF)-Flt1 pathway activity, were particularly targeted by gemcitabine when delivered through anti-Flt1 antibody-conjugated PAMAM dendrimers. In conclusion, chemotherapeutic agents complexed with dendrimers not only improve anticancer efficacy, but they also assist in the elimination of the tumor-induced myeloid cells.


Subject(s)
Dendrimers/chemistry , Deoxycytidine/analogs & derivatives , Myeloid Cells/drug effects , Pancreatic Neoplasms/metabolism , Vascular Endothelial Growth Factor Receptor-1/metabolism , Animals , Cell Line, Tumor , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Drug Delivery Systems , Humans , Male , Mice , Mice, Nude , Polyethylene Glycols/chemistry , Tissue Distribution , Gemcitabine
7.
Cytokine Growth Factor Rev ; 31: 73-81, 2016 10.
Article in English | MEDLINE | ID: mdl-27502919

ABSTRACT

Interferon (IFN)-γ is the uppermost cytokine implicated in anti-tumor immunity. With its cytostatic, pro-apoptotic and immune-provoking effects, IFN-γ plays a central role in the recognition and elimination of transformed cells. Considering well-characterized anti-tumor effects of this cytokine, many clinical trials and immunotherapy approaches have been designed to reinforce IFN-γ-mediated immunity for different types of cancer. However, the outcomes were not satisfactory and leaded to questioning of alternative actions of IFN-γ. Many regulatory pathways can be induced by IFN-γ to protect the normal tissues from collateral damage and to facilitate the re-establishment of homeostasis. Nevertheless, malignant cells can take the advantage of IFN-γ as an inducer of mediators inhibiting anti-tumor immune reactions. In addition, under the influence of tumor-derived factors, certain types of immune cells are also licensed by IFN-γ to perform regulatory actions. This review focuses on the immune modulatory functions of IFN-γ in cancer as an alternative story to be told.


Subject(s)
Interferon-gamma/immunology , Neoplasms/immunology , Humans
8.
Cancer Immunol Immunother ; 64(11): 1487-94, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26289091

ABSTRACT

The efficacy of immunotherapy in cancer patients is influenced by differences in their immune status. An evaluation of immunocompetence before therapy may help to predict therapeutic success and guide the selection of appropriate regimens. We assessed the preexisting cellular immunity against prostate-specific antigen (PSA) in untreated prostate cancer patients and healthy controls through measurement of the phenotype and function of CD8(+) T cells. Our data show that the majority of healthy men possess functional PSA-specific CD8(+) T cells in contrast to cancer patients, where <50 % showed a CD8(+) T cell response. PSA146-154-specific CD8(+) T cells of these patients had a higher expression of the activation marker CD38 and the exhaustion marker Tim-3, indicating that PSA-specific cells are exhausted. The heterogeneity of the CD8(+) T cell response against PSA in prostate cancer patients may influence their response to therapy and is a factor to be taken into account while designing and selecting treatment regimens.


Subject(s)
ADP-ribosyl Cyclase 1/analysis , CD8-Positive T-Lymphocytes/immunology , Membrane Glycoproteins/analysis , Membrane Proteins/analysis , Prostate-Specific Antigen/immunology , Prostatic Neoplasms/immunology , Aged , Hepatitis A Virus Cellular Receptor 2 , Humans , Male , Middle Aged , Prostatic Neoplasms/chemistry , Prostatic Neoplasms/therapy
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