• Journal of Life Science
• /
• v.21 no.5
• /
• pp.631-646
• /
• 2011

Mesenchymal stem cells (MSC) are multipotent and can be isolated from diverse human tissues including bone marrow, fat, placenta, dental pulp, synovium, tonsil, and the thymus. They function as regulators of tissue homeostasis. Because of their various advantages such as plasticity, easy isolation and manipulation, chemotaxis to cancer, and immune regulatory function, MSCs have been considered to be a potent cell source for regenerative medicine, cancer treatment and other cell based therapy such as GVHD. However, relating to its supportive feature for surrounding cell and tissue, it has been frequently reported that MSCs accelerate tumor growth by modulating cancer microenvironment through promoting angiogenesis, secreting growth factors, and suppressing anti-tumorigenic immune reaction. Thus, clinical application of MSCs has been limited. To understand the underlying mechanism which modulates MSCs to function as tumor supportive cells, we co-cultured human adipose tissue derived mesenchymal stem cells (ASC) with cancer cell lines H460 and U87MG. Then, expression data of ASCs co-cultured with cancer cells and cultured alone were obtained via microarray. Comparative expression analysis was carried out using DAVID (Database for Annotation, Visualization and Integrated Discovery) and PANTHER (Protein ANalysis THrough Evolutionary Relationships) in divers aspects including biological process, molecular function, cellular component, protein class, disease, tissue expression, and signal pathway. We found that cancer cells alter the expression profile of MSCs to cancer associated fibroblast like cells by modulating its energy metabolism, stemness, cell structure components, and paracrine effect in a variety of levels. These findings will improve the clinical efficacy and safety of MSCs based cell therapy.

• Tuberculosis and Respiratory Diseases
• /
• v.46 no.3
• /
• pp.327-337
• /
• 1999

Background: Reactive oxygen species are involved in multi-stage process of carcinogenesis. The moot of cancer cell lines and cancer cells in tumor tissue produce reactive oxygen species and on the other hand, the activities of catalase, Mn- and CuZn-superoxide dismutase in tumor cells are usually low. These persistent oxidative stress in tumor tissue facilitates tumor invasion and metastasis. 12-kDa thioredoxin, which regulates the intracellular redox potential with glutathione and glutaredoxin is involved in cell activation, proliferation, differentiation and redox-mediated apoptosis. It is also purified as 14-kDa and 10-kDa eooinophilic cytotoxic enhancing factor(ECEF) from human histiocytic cell(U937) and 10-kDa ECEF has more than 20 times eosinophilic stimulation activity than 14-kDa ECEF. It has been reported that adult T-cell leukemia, squamous cell carcinoma of uterine cervix, and hepatocellular carcinoma show increased amounts of human thioredoxin and thioredoxin mRNA is increased in lung cancer. In this study, we investigated the expression of conventional antioxidant enzymes such as catalase, CuZn-SOD, and glutathione peroxidase and thioredoxin in lung cancer tissue compared to adjacent normal lung tissue and the induction of thioredoxin in macrophage cells after treatment of oxidative stress and endotoxin Methods: We measured the amount of conventional antioxidant enzymes such as catalase, CuZn-SOD, and glutathione peroxidase and thioredoxin in lung cancer tissue compared to adjacent normal lung tissue by immunoblot analysis and the induction of thioredoxin in mouse monocyte-macrophage cells(RAW 264.7) by treatment of 5 ${\mu}M$ menadione and 1 ${\mu}g/ml$ endotoxin Results: On immunoblot analysis, the expression of 12-kDa thioredoxin was increased in lung cancer tissue compared to paired normal lung tissue. but the expression of catalase and CuZn-SOD were decreased in lung cancer tissue compared to paired normal tissue and the expression of glutathione peroxidase in lung cancer was variable. The expression of truncated thioredoxin was also increased in lung cancer. When mouse monocyte-macrophage cells were treated with 5 ${\mu}M$ menadione and 1 ${\mu}g/ml$ endotoxin, the expression of thioredoxin was peaked at 12 hrs and sustained to 48 hrs. Conclusion: In contrast with other conventional antioxidants, the expression of 12-kDa and truncated thioredoxin in lung cancer were increased and it is closely associated with persistent oxidative stress in tumor microenvironment. Considering especially the biological functions of truncated thioredoxin, the increased amount of truncated thioredoxin has significant role in tumor growth through cell proliferation.

• Tuberculosis and Respiratory Diseases
• /
• v.59 no.2
• /
• pp.142-150
• /
• 2005

Background : Continuous growth stimulation by various factors, as well as chronic oxidative stress, may co-exist in many solid tumors, such as lung cancer. A new family of antioxidant proteins, the peroxiredoxins (Prxs), have been implicated in the regulation of many cellular processes, including cell proliferation, differentiation and apoptosis. However, a real pathophysiological significance of Prx proteins, especially in lung disease, has not been sufficiently defined. Therefore, this study was conducted to investigate the distribution and expression of various Prx isoforms in lung cancer and other pulmonary conditions. Method : Patients diagnosed with lung cancer, and who underwent surgery at the Ajou Medical Center, were enrolled. The expressions of Prxs, Thioredoxin (Trx) and Thioredoxin reductase (TR) were analyzed using proteomic techniques and the subcellular localization of Prx proteins was studied using immunohistochemistry on normal mouse lung tissue. Result : Immunohistochemical staining has shown the isoforms of Prx I, II, III and V are predominantly expressed in bronchial and alveolar lining epithelia, as well as in the alveolar macrophages of the normal mouse lung. The isoforms of Prx I and III, and thioredoxin were also found to be over-expressed in the lung cancer tissues compared to their paired normal lung controls. There was also an increased amount of the oxidized form of Prx I, as well as a putative truncated form of Prx III, in the lung cancer samples when analyzed using 2-dimensional electrophoresis. In addition, a 43 kDa intermediate molecular weight protein band, and other high molecular weight bands of over 20 kDa, recognized by the anti-Prx I antibody, were present in the tissue extracts of lung cancer patients on 1-Dimensional electrophoresis, which require further investigation. Conclusion : The over-expressions of Prx I and III, and Trx in human lung cancer tissue, as well as their possible chaperoning function, may represent an attempt by tumor cells to adjust to their microenvironment in a manner advantageous to their survival and proliferation, while maintaining their malignant potential.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.13
• /
• pp.5181-5186
• /
• 2014

Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-${\beta}$(TGF-${\beta}$) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor microenvironment. TGF-${\beta}$ produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-${\beta}$ in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-${\beta}$ using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and $CD4^+Foxp3^+$ Treg cells, and consequently enhanced IFN-${\gamma}$ production by CTLs. Knockdown of tumor-derived TGF-${\beta}$ also significantly reduced the conversion of na$\ddot{i}$ve $CD4^+$ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-${\beta}$ suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-${\beta}$ is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-${\beta}$ may serve as a potential therapeutic approach for cancer.

• Korean Journal of Bronchoesophagology
• /
• v.2 no.2
• /
• pp.200-212
• /
• 1996

The clinical staging systems for oral squamous cell carcinoma is limited as a prognostic indicatior because of different biological characteristics of cancer in this region and variable microenvironment depending on subsites, there have been study to determine prognosis by evaluating malignancy, that is the nature of tumor cells. Many studies have been tried to determine prognostic indicator in various malignancies for the evaluation of differentiation capacity and the expression of oncogene product. EGF make a role in cellular growth and differentiation and to be essential in cellular survival. EGFR is an intergral membrane protein, stimulate cellular differentiation and hormonal secretion, and has structural homology with V-erb-B transforming protein. Recent reports have demonstrated that EGFR is overexpressed in stomach, breast, vagina, dermis, head and neck, genitourinary and lung tumors, and possibly used as a tumor marker. In head and neck region, most of studies were mainly carried out on laryngeal squamous cell carcinoma. In the present study, immunohistochemical study for EGFR and C-erb-B2 gene in paraffin sections of 45 squamous cell carcinoma in oral cavity was performed to evaluate the presense of EGFR and C- erb-B2 gene in this lesion, to evaluate them as a prognostic indicator by analysing the correlation between these expression and subsites, primary stages, clinical stages, pathologic grades, neck node metastasis, recurrences and treatment results, and to determine relation between EGFR and C-erb-B2 gene.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
• /
• v.35 no.2
• /
• pp.106-111
• /
• 2009

Bisphosphonates have been approved for Paget's disease, cancer-related hypercalcemia, bone involvement in multiple myeloma or solid tumors and osteoporosis. Although, underlying pathophysiological mechanisms remain unclear, it seems that bisphosphonates inhibit osteoclast precursor cells, modulate migratory and adhesive characteristics and induce apoptosis of osteoclasts. Furthermore impacts on angiogenesis, microenvironment and signal transduction between osteoclasts and osteoblasts. In this report, we present a case of oral bisphosphonates induced osteonecrosis of the mandible in a 84-year-old patient who received for two years. Two tapered screw vent implants(Zimmer, USA) were placed in the area of first and second molar. Two weeks later after crowns restored, some inflammatory signs and symptoms were observed on the second molar area. Sequestrum was formed and the sequestrum was removed with the implant. Frequent follow-up checks and oral hygiene maintenances were done and the first molar implant was restored. There is insufficient evidence suggests that duration of oral bisphosphonate therapy correlates with the development and severity of osteonecrosis. Therefore, dentists should not overlook the possibility of development of bisphosphonate induced osteonecrosis in patients who have taken oral forms of medication for less than three years.

• Journal of Animal Science and Technology
• /
• v.62 no.2
• /
• pp.239-246
• /
• 2020

Microorganism residing in the gut has been known to have important roles in the animal body. Microbes and host microenvironment are highly related with host's health including energy metabolism and immune system. Moreover, it reported that gut microbiome is correlated with diseases like obesity in human and dogs. There have been many studies to identify and characterize microbes and their genes in human body. However, there was little information of microbiome in companion animals. Here, we investigated microbiota communities in feaces from twenty - four Beagles (aged 2 years old) and analyzed the taxonomy profile using metagenomics to study the difference among gut microbiome based on body condition score (BCS). gDNA was isolated from feaces, sequenced and clustered. Taxonomy profiling was performed based on the NCBI database. BCS was evaluated once a week according to the description provided by World Small Animal Veterinary Association. Firmicutes phylum was the most abundant followed by Bacteroidetes, Fusobacteria, Proteobacteria and Actinobacteria. That main microbiota in gut were differently distributed based on the BCS. Fusobacteria has been known to be associated with colon cancer in human. Interestingly, Fusobacteria was in the third level from the top in healthy dog's gut microbiome. In addition, Fusobacteria was especially higher in overweight dogs which had 6 scales of BCS. Species Fusobacterium perfoetens was also more abundant when dogs were in BCS 6. It implied that F. perfoetens would be positively related with overweight in dogs. These finding would contribute to further studies of gut microbiome and their functions to improve dog's diets and health condition.

• Proceedings of the KOR-BRONCHOESO Conference
• /
• 1993.05a
• /
• pp.85-85
• /
• 1993

The clinical staging system for laryngeal cancers is not sufficient for prognosticator due to different biologic characteristics and their microenvironment according to primary sites. For determining the prognosticators, the authors peformed immunohistochemical staining to EGFR, p53 protein, and pRB in 40 cases of surgically treated squamous cell carcinomas of larynx in our institute during the past 5 years. The results are as followings; 1. The positive expression rate of p53 protein and negative expression rate of pRB showed correlations with clinical parameters. 2. The three-year survival rate for p53 protein positive cases was worse than the p53 protein negative cases. 3. Expression rate of EGFR was not correlated with the clinical parameters. As a conclusion, expression rates of p53 protein and pRB not only reflect well the biologic behavior of laryngeal cancer, but correlate closely with the tumor factors. Therefore they may be useful as the prognosticator to predict the malignant potency of laryngeal squamous cell carcinomas.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
• /
• v.27 no.4
• /
• pp.314-320
• /
• 2001

Matrix metalloproteinases have long been viewed as ideal candidates for proteinases that enables tumor cells to permeated basement membrane defenses and invade surrounding tissue. There is growing evidence that the MMPs have an expanded role, as they are important for the creation and maintenance of a microenvironment that facilitates growth and angiogenesis of tumors at primary and metastatic sites. MT-MMPs are not secreted but instead remaining attached to cell surfaces. Although not all of the MT-MMPs are fully characterized, MT-MMPs have important role in localizing and activating secreted MMPs. The MMP genes are transcriptionally responsive to a wide variety of oncogene, growth factors, cytokine, and hormones. Currently, a number of MMP inhibitors are being developed and some have reached clinical trials as anti-metastatic or anti-cancer therapies. MT1-MMP is involved in the activation of proMMP-2. MT1-MMP is significant not only as a tumor marker but as a new target for chemotherapy against cancer. The purpose of this study was to evaluate the effects of protein kinase C inhibitor(genistein) on the proliferation of HT1080 and expression of MT1-MMP mRNA. Human fibrosarcoma cell line HT1080 was cultured and divided 2 groups. The experimental group was treated with $100{\mu}M$ genistein and incubated 12h, 24h for $[3^H]-thymidine$ uptake assay and northern hybridization individually. And the control group was treated with same amount of PBS for the above procedures. $[3^H]-thymidine$ incorporation was measured with ${\beta}$ ray detector. And RT-PCR and northern blotting for MT1-MMP mRNA was performed. The results were as follows 1. $[3^H]-thymidine$ uptake was reduced in experimental group with statistical significance. 2. MT1-MMP mRNA expression was significantly reduced in experimental group. These results showed that protein kinase C inhibitor (genistein) inhibited proliferation of HT1080 and almost completely blocked transcription of MT1-MMP mRNA. So, it is possible to use the protein kinase inhibitor (genistein) as anti-metastatic and anti-proliferative agent.

• Asian Pacific Journal of Cancer Prevention
• /
• v.13 no.8
• /
• pp.4031-4036
• /
• 2012

Background: The negative signaling provided by interactions of the co-inhibitory molecule, programmed death-1 (PD-1), and its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), is a critical mechanism contributing to tumor evasion; blockade of this pathway has been proven to enhance cytotoxic activity and mediate antitumor therapy. Here we evaluated the anti-tumor efficacy of AAV-mediated delivery of the extracellular domain of murine PD-1 (sPD-1) to a tumor site. Material and Methods: An rAAV vector was constructed in which the expression of sPD-1, a known negative regulator of TCR signals, is driven by human cytomegalovirus immediate early promoter (CMV-P), using a triple plasmid transfection system. Tumor-bearing mice were then treated with the AAV/sPD1 construct and expression of sPD-1 in tumor tissues was determined by semi quantitative RT-PCR, and tumor weights and cytotoxic activity of splenocytes were measured. Results: Analysis of tumor homogenates revealed sPD-1 mRNA to be significantly overexpressed in rAAV/sPD-1 treated mice as compared with control levels. Its use for local gene therapy at the inoculation site of H22 hepatoma cells could inhibit tumor growth, also enhancing lysis of tumor cells by lymphocytes stimulated specifically with an antigen. In addition, PD-1 was also found expressed on the surfaces of activated CD8+ T cells. Conclusion: This study confirmed that expression of the soluble extracellular domain of PD-1 molecule could reduce tumor microenvironment inhibitory effects on T cells and enhance cytotoxicity. This suggests that it might be a potential target for development of therapies to augment T-cell responses in patients with malignancies.