• BMB Reports
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• 제55권2호
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• pp.81-86
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• 2022

Macrophages are a major cellular component of innate immunity and are mainly known to have phagocytic activity. In the tumor microenvironment (TME), they can be differentiated into tumor-associated macrophages (TAMs). As the most abundant immune cells in the TME, TAMs promote tumor progression by enhancing angiogenesis, suppressing T cells and increasing immunosuppressive cytokine production. N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene, whose expression is down-regulated in various cancers. However, the effect of NDRG2 on the differentiation of macrophages into TAMs in breast cancer remains elusive. In this study, we investigated the effect of NDRG2 expression in breast cancer cells on the differentiation of macrophages into TAMs. Compared to tumor cell-conditioned medium (TCCM) from 4T1-mock cells, TCCM from NDRG2-over-expressing 4T1 mouse breast cancer cells did not significantly change the morphology of RAW 264.7 cells. However, TCCM from 4T1-NDRG2 cells reduced the mRNA levels of TAM-related genes, including MR1, IL-10, ARG1 and iNOS, in RAW 264.7 cells. In addition, TCCM from 4T1-NDRG2 cells reduced the expression of TAM-related surface markers, such as CD206, in peritoneal macrophages (PEM). The mRNA expression of TAM-related genes, including IL-10, YM1, FIZZ1, MR1, ARG1 and iNOS, was also downregulated by TCCM from 4T1-NDRG2 cells. Remarkably, TCCM from 4T1-NDRG2 cells reduced the expression of PD-L1 and Fra-1 as well as the production of GM-CSF, IL-10 and ROS, leading to the attenuation of T cell-inhibitory activity of PEM. These data showed that compared with TCCM from 4T1-mock cells, TCCM from 4T1-NDRG2 cells suppressed the TAM differentiation and activation. Collectively, these results suggest that NDRG2 expression in breast cancer may reduce the differentiation of macrophages into TAMs in the TME.

• BMB Reports
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• 제57권4호
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• pp.167-175
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• 2024

Cancer progression is driven by genetic mutations, environmental factors, and intricate interactions within the tumor microenvironment (TME). The TME comprises of diverse cell types, such as cancer cells, immune cells, stromal cells, and neuronal cells. These cells mutually influence each other through various factors, including cytokines, vascular perfusion, and matrix stiffness. In the initial or developmental stage of cancer, neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor are associated with poor prognosis of various cancers by communicating with cancer cells, immune cells, and peripheral nerves within the TME. Over the past decade, research has been conducted to prevent cancer growth by controlling the activation of neurotrophic factors within tumors, exhibiting a novel attemt in cancer treatment with promising results. More recently, research focusing on controlling cancer growth through regulation of the autonomic nervous system, including the sympathetic and parasympathetic nervous systems, has gained significant attention. Sympathetic signaling predominantly promotes tumor progression, while the role of parasympathetic signaling varies among different cancer types. Neurotransmitters released from these signalings can directly or indirectly affect tumor cells or immune cells within the TME. Additionally, sensory nerve significantly promotes cancer progression. In the advanced stage of cancer, cancer-associated cachexia occurs, characterized by tissue wasting and reduced quality of life. This process involves the pathways via brainstem growth and differentiation factor 15-glial cell line-derived neurotrophic factor receptor alpha-like signaling and hypothalamic proopiomelanocortin neurons. Our review highlights the critical role of neurotrophic factors as well as central nervous system on the progression of cancer, offering promising avenues for targeted therapeutic strategies.

• Asian Pacific Journal of Cancer Prevention
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• 제13권11호
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• pp.5909-5913
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• 2012

Aims: We aimed to analyze the phenotype of tumor-infiltrating lymphocytes (TILs) and non-tumor infiltrating lymphocytes (NILs) in HCC and non-tumor tissues, and evaluate relationships between changes in these cells and the prognosis of HCC. Methods: Lymphocytes were isolated from HCC and corresponding non-tumor tissues and tested by flow cytometry. For comparison, clinical parameters were analyzed. Results: Compared with the non-tumor tissue, tumor tissue had a lower intensity of NK, NKT andCD8+T cell infiltration. TILs had higher intensity of CD4+CD25+Foxp3+regulatory T cell (Treg cells) infiltration compared with that in NILs. The prevalence of Treg cells was associated with fewer CD8 + T lymphocytes in the HCC immune microenvironment. The frequencies of NK cells and CD8+T cells in TILs of HCC patients with metastasis less than 12 months were lower than those without metastasis. However, the frequency of Treg cells was higher than those without metastasis. Conclusion: These results suggest that the frequencies of CD8+T, NK and NKT cells as well as Treg cells in the tumor tissue of HCC are significantly associated with patient survival, and could be applied as predictive indicators for HCC prognosis.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8225-8228
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• 2014

Glioma is one of the most common tumors in China and chemotherapy is critical for its treatment. Recent studies showed that benzyl isothiocyanate (BITC) could inhibit the growth of glioma cells, but the mechanisms are not fully understood. This study explored the inhibitory effect of BITC on invasion and angiogenesis of U87MG human glioma cells in vitro and in vivo, as well as potential mechanisms. It was found that BITC could inhibit invasion and angiogenesis of human glioma U87MG cells by inducing cell cycle arrest at phase G2/M. It also was demonstrated that BITC decreased expression of cyclin B1, p21, MMP-2/9, VE-cadherin, CD44, CXCR4 and MTH1, the activity of the telomerase and $PKC{\zeta}$ pathway. Microarray analysis was thus useful to explore the potential target genes related to tumorigenic processes. BITC may play important roles in the inhibition of invasion and angiogenesis of human glioma cells.

• IMMUNE NETWORK
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• 제14권6호
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• pp.296-306
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• 2014

There is growing evidence that crosstalk between mantle cell lymphoma (MCL) cells and stromal microenvironments, such as bone marrow and secondary lymphoid tissues, promotes tumor progression by enhancing survival and growth as well as drug resistance of MCL cells. Recent advances in the understanding of lymphoma microenvironment have led to the identification of crucial factors involved in the crosstalk and subsequent generation of their targeted agents. In the present study, we evaluated the combinatory effect of blocking antibodies (Ab) targeting CXCR4 and VLA-4, both of which were known to play significant roles in the induction of environment-mediated drug resistance (EMDR) in MCL cell line, Jeko-1. Simultaneous treatment with anti-CXCR4 and anti-VLA-4 Ab not only reduced the migration of Jeko-1 cells into the protective stromal cells, but also enhanced sensitivity of Jeko-1 to a chemotherapeutic agent to a greater degree than with either Ab alone. These combinatorial effects were associated with decreased phosphorylation of ERK1/2, AKT and NF-${\kappa}B$. Importantly, drug resistance could not be overcome once the adhesion of Jeko-1 to the stromal occurred despite the combined use of Abs, suggesting that the efforts to mitigate migration of MCLs should be attempted as much as possible. Our results provide a basis for a future development of therapeutic strategies targeting both CXCR4 and VLA-4, such as Ab combinations or bispecific antibodies, to improve treatment outcomes of MCL with grave prognosis.

• Journal of Veterinary Science
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• 제22권3호
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• pp.25.1-25.16
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• 2021

Background: Malignant lymphoma is the most common hematopoietic malignancy in dogs, and relapse is frequently seen despite aggressive initial treatment. In order for the treatment of these recurrent lymphomas in dogs to be effective, it is important to choose a personalized and sensitive anticancer agent. To provide a reliable tool for drug development and for personalized cancer therapy, it is critical to maintain key characteristics of the original tumor. Objectives: In this study, we established a model of hybrid tumor/stromal spheroids and investigated the association between canine lymphoma cell line (GL-1) and canine lymph node (LN)-derived stromal cells (SCs). Methods: A hybrid spheroid model consisting of GL-1 cells and LN-derived SC was created using ultra low attachment plate. The relationship between SCs and tumor cells (TCs) was investigated using a coculture system. Results: TCs cocultured with SCs were found to have significantly upregulated multidrug resistance genes, such as P-qp, MRP1, and BCRP, compared with TC monocultures. Additionally, it was revealed that coculture with SCs reduced doxorubicin-induced apoptosis and G2/M cell cycle arrest of GL-1 cells. Conclusions: SCs upregulated multidrug resistance genes in TCs and influenced apoptosis and the cell cycle of TCs in the presence of anticancer drugs. This study revealed that understanding the interaction between the tumor microenvironment and TCs is essential in designing experimental approaches to personalized medicine and to predict the effect of drugs.

• Asian Pacific Journal of Cancer Prevention
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• 제15권23호
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• pp.10115-10119
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• 2015

Purpose: The aim of this study was to investigate effects of adipose-derived mesenchymal stem cells (AMSCs) on radioresistance of breast cancer cells. Materials and Methods: MTT assays were used to detect any influence of AMSC supernatants on proliferation of breast cancer cells; cell migration assays were used to determine the effect of breast cancer cells on the recruitment of AMSCs; the cell survival fraction post-irradiation was assessed by clonogenic survival assay; ${\gamma}$-H2AX foci number post-irradiation was determined via fluorescence microscopy; and expression of IGF-1R was detected by Western blotting. Results: AMSC supernatants promoted proliferation and radioresistance of breast cancer cells. Breast cancer cells could recruit AMSCs, especially after irradiation. IGF-1 derived from AMSCs might be responsible for the radioresistance of breast cancer cells. Conclusions: Our results suggest that AMSCs in the tumor microenvironment may affect the outcome of radiotherapy for breast cancer in vitro.

• Asian Pacific Journal of Cancer Prevention
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• 제13권4호
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• pp.1305-1310
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• 2012

Breast cancer cells undergo transformation when they spread into surrounding tissues. Studies have shown that cancer cells undergo surface alterations and interact with the surrounding microenvironment during the invasion process. The aim of the present study was to analyse these cancer cell surface alterations and interactions of cancer cells and stroma. Twenty 1-methyl-1-nitrosourea-induced breast cancer samples taken from five rats were fixed in McDowell-Trump fixative and then washed in 0.1 M phosphate buffer. The samples were then treated with osmium tetroxide before being washed in distilled water and subsequently dehydrated through graded ethanols. The dehydrated samples were immersed in hexamethyldisilazane (HMDS), then following removal of excess HMDS, the samples were air dried at room temperature in a dessicator. The dried samples were mounted onto specimen stubs and coated with gold coater before being viewed under a scanning electron microscope. We detected the presence of membrane ruffles on the surface of cancer cells and the formation of unique surface membrane protrusions to enhance movement and adhesion to the surrounding stroma during the process of invasion. Advancing cancer cells demonstrated formation of lamellipodia and invadopodia. The stroma at the advancing edge was desmoplastic with many collagen fibres laid down near the cancer cells. Our data suggest that all of these abnormalities could act as hallmarks of invasiveness for breast cancer.

• BMB Reports
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• 제45권12호
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• pp.677-685
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• 2012

In the process of tumorigenesis, normal cells are remodeled to cancer cells and protein expression patterns are changed to those of tumor cells. A newly formed tumor microenvironment elicits the immune system and, as a result, a humoral immune response takes place. Although the tumor antigens are undetectable in sera at the early stage of tumorigenesis, the nature of an antibody amplification response to antigens makes tumor-associated autoantibodies as promising early biomarkers in cancer diagnosis. Moreover, the recent development of proteomic techniques that make neo-epitopes of tumor-associated autoantigens discovered concomitantly has opened a new area of 'immuno-proteomics', which presents tumor-associated autoantibody signatures and confers information to redefine the process of tumorigenesis. In this article, the strategies recently used to identify and validate serum autoantibodies are outlined and tumor-associated antigens suggested until now as diagnostic/prognostic biomarkers in various tumor types are reviewed. Also, the meaning of autoantibody signatures and their clinical utility in personalized medicine are discussed.

• Molecules and Cells
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• 제46권3호
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• pp.176-186
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• 2023

The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex. This mini review focuses on key studies describing how the KEAP1/NRF2 pathway affects cancer at different phases. The data compiled suggest that the roles of KEAP1/NRF2 in cancer are highly dependent on context; specifically, the model used (carcinogen-induced vs genetic), the tumor type, and the stage of cancer. Moreover, emerging data suggests that KEAP1/NRF2 is also important for regulating the tumor microenvironment and how its effects are amplified either by epigenetics or in response to co-occurring mutations. Further elucidation of the complexity of this pathway is needed in order to develop novel pharmacological tools and drugs to improve patient outcomes.