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1.
Surg Case Rep ; 10(1): 95, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38652340

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide, and screening colonoscopy has led to a decreasing incidence rate. However, the incidence of CRC is increasing among young people, especially adolescents and young adults (AYAs) who are not routinely screened. Although CRC is the fourth most common cancer among AYAs, it is extremely rare. In younger patients, CRC is often diagnosed later, and the proportion of patients with advanced CRC is higher than that in older patients. We herein present a case of poorly differentiated mucinous carcinoma of the ascending colon complicated by bilateral ovarian mature cystic teratomas (MCTs) in an AYA. CASE PRESENTATION: A 17-year-old female patient presented with a chief complaint of abdominal pain and diarrhea that had persisted for more than 3 years. Colonoscopy revealed circumferential wall thickening of the ascending colon, and colonic biopsy revealed a mucous mass and findings of adenocarcinoma, predominantly signet ring cell carcinoma. Abdominal computed tomography (CT) and pelvic magnetic resonance imaging (MRI) showed bilateral ovarian tumors. Laparoscopic right hemicolectomy and enucleation of bilateral ovarian tumors were performed. Although the ascending colon cancer formed a large mass, there were no signs of peritoneal dissemination or direct invasion to the surrounding organs. Microscopically, the ascending colon was a poorly differentiated mucinous carcinoma with signet ring cell carcinoma and lymph node metastasis (9/42). The ovarian tumors were diagnosed as MCTs without any malignant components. The pathological diagnosis was ascending colon cancer (pT4aN2bM0, pStage IIIC) and bilateral ovarian MCTs. Microsatellite instability (MSI) testing was negative, and there were no gene mutations in either RAS or BRAF. Postoperative adjuvant chemotherapy with oxaliplatin and 5-FU was started. CONCLUSIONS: We presented a case of locally advanced ascending colon cancer in a 17-year-old female patient. CRC rarely occurs in AYAs. However, the incidence has gradually increased in recent years. It should be considered as a differential diagnosis for young patients with long-term abdominal symptoms of unknown cause.

2.
Cancer Sci ; 114(6): 2220-2229, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36748310

ABSTRACT

Tumor-associated macrophages (TAMs) are the most prominent immune cells in the breast cancer microenvironment, and the protumor functions of TAMs are thought to affect cancer progression and resistance to anticancer therapy. Numerous studies using human breast cancer samples, cell lines, and murine breast cancer models have revealed details of the mechanisms by which the protumor functions of TAMs are activated. Recent advances have highlighted the significant involvement of TAMs in the resistance of breast cancer cells to immunotherapy. Tumor-associated macrophages express a number of immunosuppressive genes, and single-cell sequence analyses of human and murine cancer samples have helped elucidate the mechanism of TAM-induced immunosuppression. As TAMs are considered suitable targets for anticancer therapies, we summarized the protumor functions of TAMs and the potential of anticancer therapies targeting TAMs, with a focus on breast cancer research.


Subject(s)
Breast Neoplasms , Humans , Animals , Mice , Female , Breast Neoplasms/pathology , Macrophages/metabolism , Phenotype , Immunotherapy , Immune Tolerance , Tumor Microenvironment
3.
Sci Rep ; 12(1): 12007, 2022 07 14.
Article in English | MEDLINE | ID: mdl-35835809

ABSTRACT

Ever since immune checkpoint inhibitors have been approved for anti-cancer therapy in several cancers, including triple-negative breast cancer, the significance of programmed death-1 ligand 1 (PD-L1) expression in the tumor immune microenvironment has been a topic of interest. In the present study, we investigated the detailed mechanisms of PD-L1 overexpression on tumor-associated macrophages (TAMs) in breast cancer. In in vitro culture studies using human monocyte-derived macrophages, lymphocytes, and breast cancer cell lines, PD-L1 overexpression on macrophages was induced by the conditioned medium (CM) of activated lymphocytes, but not that of cancer cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) derived from activated lymphocytes was found to be involved in PD-L1 overexpression, in addition to interferon (IFN)-γ, via STAT3 pathway activation. Macrophages suppressed lymphocyte activation, and this inhibition was impaired by PD-1 blocking. The CM of activated lymphocytes also induced the overexpression of PD-L2, but GM-CSF did not affect PD-L2 expression. In the murine E0771 breast cancer model, anti-GM-CSF therapy did not affect PD-L1 expression on TAMs, and the mechanisms of PD-L1 expression on TAMs might differ between humans and mice. However, not only PD-L1, but also PD-L2 was overexpressed on TAMs in the E0771 tumor model, and their expression levels were significantly lower in the tumors in nude mice than in wild-type mice. Anti-PD-L1 antibody and anti-PD-L2 antibody synergistically inhibited E0771 tumor development. In conclusion, PD-L1 and PD-L2 were overexpressed on TAMs, and they potentially contributed to immunosuppression. The GM-CSF-STAT3 pathway is thought to represent a new mechanism of PD-L1 overexpression on TAMs in human breast cancer microenvironment.


Subject(s)
Breast Neoplasms , Granulocyte-Macrophage Colony-Stimulating Factor , Animals , B7-H1 Antigen , Female , Humans , Ligands , Mice , Mice, Nude , Tumor Microenvironment , Tumor-Associated Macrophages
4.
Anticancer Res ; 41(9): 4249-4258, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34475044

ABSTRACT

BACKGROUND/AIM: Recent studies have indicated the clinical significance of tumor-associated macrophages (TAMs) in breast cancer; however, the detailed mechanisms of cell-cell interactions between TAMs and cancer cells remain unclear. MATERIALS AND METHODS: In vitro cell culture studies using human monocyte-derived macrophages and breast cancer cell lines were performed to test which cytokines would be involved in cell-cell interactions between cancer cells and macrophages. In addition, studies using human resected samples and animal breast cancer models were performed to examine the significance of TAMs in cancer development. RESULTS: Osteopontin, HB-EGF, and IL-6 were suggested to be macrophage-derived growth factors for breast cancer cells. FROUNT inhibitor significantly blocked TAM infiltration and subcutaneous tumor growth in an E0771 mouse breast cancer model. CONCLUSION: TAMs express growth factors, such as osteopontin, for cancer cells, and targeting of TAM infiltration might be a promising approach for anti-breast cancer therapy.


Subject(s)
Breast Neoplasms/pathology , Heparin-binding EGF-like Growth Factor/genetics , Interleukin-6/genetics , Macrophages/cytology , Osteopontin/genetics , Tumor-Associated Macrophages/cytology , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Communication , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cells, Cultured , Coculture Techniques , Female , Heparin-binding EGF-like Growth Factor/metabolism , Humans , Interleukin-6/metabolism , MCF-7 Cells , Macrophages/metabolism , Mice , Neoplasm Transplantation , Osteopontin/metabolism , Tumor Microenvironment , Tumor-Associated Macrophages/metabolism , Tumor-Associated Macrophages/pathology
5.
Pathol Int ; 68(12): 685-693, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30516869

ABSTRACT

Recent findings indicate CD169-positive lymph node sinus macrophages (LySMs) in the regional lymph nodes (RLNs) play an important role in anti-cancer immunity. In the present study, we investigated the correlation between CD169 expression in RLNs and clinicopathologic factors. Higher CD169 expression in LySMs was significantly associated with longer cancer-specific survival (CSS). The density of tumor-infiltrating lymphocytes (TILs) in the cancer nest and CD169 expression on LySMs were positively associated in patients who underwent pretreatment. As CD169 expression is thought to reflect a high interferon signature in RLNs, we tried to identify immunity-related genes that are up-regulated by interferon in macrophages as well as CD169. Indoleamine 2,3-dioxygenase (IDO1) was found to be elevated by interferon, and expression of IDO1 was tested using immunohistochemistry. IDO1 expression on LySMs was positively correlated with CD169 expression; however, there was no significant correlation between IDO1 and clinicopathologic factors. These results suggest that high expression of CD169 in LySMs reflects a high potential for anti-cancer immune responses in esophageal cancer patients and that monitoring CD169 expression would be useful for evaluating the potential of anti-cancer immune reactions.


Subject(s)
Esophageal Neoplasms/immunology , Lymph Nodes/immunology , Macrophages/immunology , Sialic Acid Binding Ig-like Lectin 1/biosynthesis , Adult , Aged , Biomarkers, Tumor/analysis , Esophageal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Prognosis , Sialic Acid Binding Ig-like Lectin 1/immunology
6.
J Clin Exp Hematop ; 58(2): 95-101, 2018.
Article in English | MEDLINE | ID: mdl-29998979

ABSTRACT

Recent progress in anti-tumor immunotherapy has focused on the significance of the tumor microenvironment in tumor progression and resistance to chemo/radio-therapy. Myeloid cells such as macrophages are predominant stromal components in hematological malignancies. In the present study, we investigated the regulation of programmed death-1 (PD-1) ligand expression in primary central nervous system lymphoma (PCNSL) using PCNSL cell lines and human monocyte-derived macrophages. TK PCNSL cell line-derived soluble factors induced overexpression of PD-1 ligands, indoleamine 2,3-dioxygenase (IDO1), and several other cytokines in macrophages. The expression of PD-1 ligands was dependent on the activation of signal transducer and activator of transcription 3. PD-L1 and IDO1 were overexpressed by macrophage/microglia in PCNSL tissues, and gene expression profiling indicated that IDO1 expression was positively correlated with the expression of macrophage and lymphocyte markers. Macrophage-derived factors did not influence the proliferation or chemo-sensitivity of cell lines. These data suggest that the expression of immunosuppressive molecules, including PD-1 ligands and IDO1, by macrophage/microglia may be involved in immune evasion of lymphoma cells.


Subject(s)
B7-H1 Antigen/immunology , Central Nervous System Neoplasms/immunology , Gene Expression Regulation, Neoplastic/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Lymphoma/immunology , Macrophages/immunology , Microglia/immunology , Neoplasm Proteins/immunology , Tumor Escape , Cell Line, Tumor , Central Nervous System Neoplasms/pathology , Female , Humans , Lymphoma/pathology , Macrophages/pathology , Male , Microglia/pathology
7.
Sci Rep ; 8(1): 5927, 2018 04 12.
Article in English | MEDLINE | ID: mdl-29651144

ABSTRACT

Cisplatin-induced acute kidney injury (AKI) has been recognized as one of cisplatin's serious side effects, limiting its use in cancer therapy. Sirtuin 1 (SIRT1) and SIRT3 play protective roles against cisplatin-induced kidney injury. However, the role of SIRT7 in cisplatin-induced kidney injury is not yet known. In this study, we found that Sirt7 knockout (KO) mice were resistant to cisplatin-induced AKI. Furthermore, our studies identified that loss of SIRT7 decreases the expression of tumor necrosis factor-α (TNF-α) by regulating the nuclear expression of the transcription factor nuclear factor kappa B. It has been reported that cisplatin-induced nephrotoxicity is mediated by TNF-α. Our results indicate that SIRT7 plays an important role in cisplatin-induced AKI and suggest the possibility of SIRT7 as a novel therapeutic target for cisplatin-induced nephrotoxicity.


Subject(s)
Acute Kidney Injury/genetics , Cisplatin/adverse effects , Inflammation/genetics , Sirtuins/genetics , Acute Kidney Injury/chemically induced , Acute Kidney Injury/pathology , Animals , Apoptosis/genetics , Cisplatin/therapeutic use , Humans , Inflammation/chemically induced , Inflammation/pathology , Kidney/drug effects , Kidney/injuries , Kidney/pathology , Mice , Mice, Knockout , Neoplasms/complications , Neoplasms/drug therapy , Oxidative Stress/drug effects , Oxidative Stress/genetics , Sirtuin 3 , Tumor Necrosis Factor-alpha/genetics
8.
EBioMedicine ; 30: 94-104, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29559295

ABSTRACT

Glioblastoma (GBM) usually develops in adult brain white matter. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and periphery by miRNA microarray. The top three of miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathologically oligodendrocyte lineage cells were increased in the border, where macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1ß, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a promising target for prevention of recurrence.


Subject(s)
Brain Neoplasms/pathology , Glioma/pathology , Macrophages/pathology , Microglia/pathology , Neoplastic Stem Cells/pathology , Oligodendrocyte Precursor Cells/pathology , Stem Cell Niche , Brain Neoplasms/genetics , Cell Communication/drug effects , Cell Communication/genetics , Cell Line, Tumor , Cell Lineage/drug effects , Cell Survival/drug effects , Culture Media, Conditioned/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Glioma/genetics , Humans , Macrophages/drug effects , Macrophages/metabolism , MicroRNAs/metabolism , Microglia/drug effects , Microglia/metabolism , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Oligodendrocyte Precursor Cells/drug effects , Oligodendrocyte Precursor Cells/metabolism , Spheroids, Cellular/drug effects , Spheroids, Cellular/metabolism , Spheroids, Cellular/pathology , Stem Cell Niche/drug effects , White Matter/pathology
9.
Cancer Sci ; 108(8): 1693-1700, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28574667

ABSTRACT

Recent studies have indicated the clinical significance of tumor-associated macrophages (TAM) in several malignant tumors including breast cancer. Although recent studies have focused on CD68-positive or CD163-positive TAM in breast cancer, no study has investigated the significance of CD204-positive TAM in breast cancer. We found that CD204 expression on macrophages was evaluated following stimulation with the conditioned medium (CM) of breast cancer cell lines. Paraffin sections of 149 breast cancer samples which were diagnosed as invasive ductal carcinoma were immunohistochemically analyzed for CD68, CD163 and CD204 expression. The results of analyses indicated that a high number of CD204-positive TAM was associated with worse clinical prognoses, including relapse-free survival, distant relapse-free survival and breast cancer-specific survival; however, neither the numbers of CD68-positive or CD163-positive TAM were associated with clinical courses. Of the clinicopathological factors investigated, estrogen receptor, Ki-67 index, hormone subtype, and histological grade were significantly related to the increased number of CD163-positive and CD204-positive TAM. These data indicate the clinical significance of CD204-positive TAM in breast cancer progression and CD204 is a marker for predicting clinical prognosis in breast cancer.


Subject(s)
Coculture Techniques/methods , Macrophages/cytology , Macrophages/metabolism , Scavenger Receptors, Class A/metabolism , Triple Negative Breast Neoplasms/metabolism , Cell Line, Tumor , Culture Media, Conditioned/pharmacology , Female , Humans , MCF-7 Cells , Macrophages/pathology , Middle Aged , Prognosis , Survival Analysis , Triple Negative Breast Neoplasms/pathology , Up-Regulation
10.
PLoS One ; 11(11): e0166680, 2016.
Article in English | MEDLINE | ID: mdl-27861544

ABSTRACT

The immune status of patients can impact on the clinical course of cancer. Lymph node (LN) macrophages play critical roles in anti-cancer immunity via the activation of cytotoxic T-lymphocytes (CTLs). In this study, the prognostic significance of CD169+ LN macrophages was examined in patients with breast cancer. For this purpose the number of CD169+ cells and their ratio relative to total macrophages (CD68+) in regional LNs (RLNs), as well as the number of CD8+ CTLs in tumor tissues, were investigated using immunohistochemistry of paraffin-embedded tissue samples from 146 patients with breast cancer. The association of these data with clinicopathological factors was then analyzed. The number of cells positive for the pan-macrophage marker CD68 remained relatively uniform, while the number of CD169+ cells varied across all cases. Moreover, a high density of CD169+ cells correlated with early clinical stage and no LN metastasis, while a higher CD169+ to CD68+ ratio was significantly associated with small tumor size and a low Ki-67+ rate. There was also a significant correlation between the number of CD8+ CTLs and that of CD169+ macrophages in high grade breast cancer cases with a Ki-67 index greater than 40%. However, neither the density nor the ratio of CD169+ cells, nor the density of CD8+ CTLs, were associated with relapse-free survival, distant relapse-free survival, or breast cancer-specific survival. These findings suggest that CD169+ macrophages in RLNs might be a useful marker for assessing clinical stage, including LN states, in patients with breast cancer.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Lymph Nodes/metabolism , Lymph Nodes/pathology , Macrophages/metabolism , Sialic Acid Binding Ig-like Lectin 1/metabolism , Adult , Biomarkers , Breast Neoplasms/mortality , Breast Neoplasms/surgery , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Female , Follow-Up Studies , Humans , Immunohistochemistry , Lymphatic Metastasis , Macrophages/immunology , Middle Aged , Neoplasm Staging , Prognosis , Survival Analysis , Tumor Burden , Young Adult
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