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1
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Ozkara G, Ceviz AB, Eronat AP, Pehlevan Karabiyik F, Candan G, Ozturk O, Yilmaz-Aydogan H. Cytotoxic and anti-migratory effects of polyphenolic compounds on breast cancer cells by altering Jam-A, LFA-1, and VLA-4 gene expression. Nat Prod Res 2025:1-12. [PMID: 40292555 DOI: 10.1080/14786419.2025.2494629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 03/18/2025] [Accepted: 04/12/2025] [Indexed: 04/30/2025]
Abstract
This study represents the initial research of the effects of a combination of the largest number (13) of different polyphenic substances (PFK5120), formulated based on the propolis content on cell viability, migration and expression of lymphocyte function-associated antigen-1 (LFA-1), very late antigen-4 (VLA-4) and junction adhesion molecule A (Jam-A) in breast cancer (BC) cells. PFK5120 negatively affected cell viability at a 5% concentration as compared with unexposed ones (p < 0.001). Treatment with 20% PFK5120 for 48h down-regulated Jam-A in MCF-7 and MCF-10A, up-regulated LFA-1 in MCF-10A and MDA-MB-231, and down-regulated VLA-4 in MCF-10A and MDA-MB-231 (p < 0.001). Furthermore, migration was found to be inhibited by PFK5120 at varying doses and times. Migration was completely inhibited by 35% PFK5120 treatment in MDA-MB-231, while even lower concentrations (10%) were effective in MCF-7. Current findings indicate that PFK5120 represents a valuable natural component of BC therapy through its cytotoxic and anti-migratory effects.
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Affiliation(s)
- Gulcin Ozkara
- Aziz Sancar Institute of Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
- Faculty of Medicine, Department of Medical Biology, Bezmialem Vakif University, Istanbul, Turkey
| | - Ayse Begum Ceviz
- Aziz Sancar Institute of Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
- Faculty of Medicine, Department of Medical Genetics, Istanbul Health & Technology University, Istanbul, Turkey
| | - Allison Pinar Eronat
- Aziz Sancar Institute of Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
- Department of Molecular Biology and Genetics, Halic University, Istanbul, Turkey
| | - Funda Pehlevan Karabiyik
- Aziz Sancar Institute of Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
- Departments of Medical Laboratory Techniques, Vocational School of Health Services, Istanbul Gelisim University, Istanbul, Turkey
| | - Gonca Candan
- Aziz Sancar Institute of Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
| | - Oguz Ozturk
- Aziz Sancar Institute of Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
| | - Hulya Yilmaz-Aydogan
- Aziz Sancar Institute of Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
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Strell C, Lang K, Niggemann B, Zaenker KS, Entschladen F. Neutrophil granulocytes promote the migratory activity of MDA-MB-468 human breast carcinoma cells via ICAM-1. Exp Cell Res 2009; 316:138-48. [PMID: 19747913 DOI: 10.1016/j.yexcr.2009.09.003] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2009] [Revised: 08/26/2009] [Accepted: 09/02/2009] [Indexed: 12/15/2022]
Abstract
Tumor infiltrating neutrophil granulocytes do not only exhibit tumor eliminating functions but also promote tumor progression. We have recently shown that neutrophil granulocytes can serve as linking cells for the adhesion of MDA-MB-468 breast carcinoma cells to pulmonary endothelium. Neutrophil granulocytes but not MDA-MB-468 cells express beta(2)-integrins, the ligands of the intercellular adhesion molecule (ICAM)-1, whereas ICAM-1 is strongly expressed on MDA-MB-468 cells. Consequently, the herein presented study was performed to investigate if this interaction has also an influence on the migratory activity of the tumor cells and whether ICAM-1 signaling plays a role in this process, too. We found that the continuous release of interleukin-8 (IL-8) and GRO-alpha by MDA-MB-468 cells increases the migratory activity of neutrophil granulocytes and attracts these cells towards the tumor cells which enables direct cell-cell interactions. These interactions in turn increase the migratory activity of the tumor cells in an ICAM-1 clustering-dependent mechanism since transfection of the tumor cells with specific siRNA against ICAM-1 abolished the effect. Moreover, ICAM-1 cross-linking on tumor cells induces the phosphorylation of focal adhesion components such as focal adhesion kinase and paxillin via src kinase as well as the activation of the p38 MAPK pathway via Rho kinase in a time-dependent manner. Our results provide evidence that ICAM-1 is coupled to intracellular signaling pathways involved in tumor cell migration. Thus, neutrophil granulocytes can act as modulators of the metastatic capability of tumor cells by ligation of ICAM-1.
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Affiliation(s)
- Carina Strell
- Institute of Immunology, Witten/Herdecke University, Stockumer Street 10, 58448 Witten, Germany
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3
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Watanabe M, Miyajima N, Igarashi M, Endo Y, Watanabe N, Sugano S. Sodium phenylacetate inhibits the Ras/MAPK signaling pathway to induce reduction of the c-Raf-1 protein in human and canine breast cancer cells. Breast Cancer Res Treat 2008; 118:281-91. [PMID: 18953652 DOI: 10.1007/s10549-008-0215-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2008] [Accepted: 09/29/2008] [Indexed: 12/30/2022]
Abstract
An aromatic fatty acid, phenylacetate (PA), has been shown to have cytostatic, antitumor and cell differentiation-inducing effects on various kinds of tumors. Previously, we have demonstrated cell growth inhibition, malignant phenotype reduction and cell differentiation effects of sodium phenylacetate (NaPA) treatment in a canine mammary tumor cell line. To clarify the molecular mechanism of these effects, we examined the expression of Ras/MAPK signaling pathway-related molecules in human and canine breast cancer cell lines, and found that the level of c-Raf-1 protein was reduced by 5, 10 and 20 mM of NaPA treatments, though Ras activation was maintained. Dephosphorylation of c-Raf-1 at Serine (Ser) 259, Ser 338, and Ser 621 were also seen in NaPA-treated cells. Downstream factors in the pathway, such as mitogen-activated protein kinase/ERK kinase (MEK)1/2 and ERK1/2, showed decreased activity, and accordingly, expressions of cyclinD1, c-myc, and inactivation of p90 ribosomal S6 kinase (RSK), which are MAPK targets, were reduced. We also observed the reduction of cell-cycle-promoted molecules, such as cdc1/cdk2, cdk4, PCNA cyclin A, and cyclin B, and the increased expression of p27kip1. Furthermore, expression of an epithelial marker, E-cadherin, was increased by NaPA treatment. These results suggest that one of the molecular targets of NaPA treatment was the reduction of c-Raf-1 protein, and that its reduction results in the decrease of malignant characteristics of tumor cells through blockage of the Ras/MAPK signaling pathway.
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Affiliation(s)
- Manabu Watanabe
- Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
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4
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Mills PJ, Ancoli-Israel S, Parker B, Natarajan L, Hong S, Jain S, Sadler GR, von Känel R. Predictors of inflammation in response to anthracycline-based chemotherapy for breast cancer. Brain Behav Immun 2008; 22:98-104. [PMID: 17706918 PMCID: PMC2199880 DOI: 10.1016/j.bbi.2007.07.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2007] [Revised: 07/06/2007] [Accepted: 07/06/2007] [Indexed: 10/22/2022] Open
Abstract
Although chemotherapy for breast cancer can increase inflammation, few studies have examined predictors of this phenomenon. This study examined potential contributions of demographics, disease characteristics, and treatment regimens to markers of inflammation in response to chemotherapy for breast cancer. Thirty-five women with stage I-III-A breast cancer (mean age 50 years) were studied prior to cycle 1 and prior to cycle 4 of anthracycline-based chemotherapy. Circulating levels of inflammatory markers with high relevance to breast cancer were examined, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), Interleukin-1 receptor antagonist (IL1-RA), vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), Interleukin- (IL-6), soluble P-selectin (sP-selectin), and von Willebrand factor (vWf). Chemotherapy was associated with elevations in VEGF (p < or = 0.01), sICAM-1 (p < or = 0.01), sP-selectin (p < or = 0.02) and vWf (p < or = 0.05). Multiple regression analysis controlling for age and body mass index (BMI) showed that higher post-chemotherapy levels of inflammation were consistently related to higher pre-chemotherapy levels of inflammation (ps < or =0.05) as well as to certain disease characteristics. Post-chemotherapy IL-6 levels were higher in patients who had larger tumors (p < or = 0.05) while post-chemotherapy VEGF levels were higher in patients who had smaller tumors (p < or = 0.05). Post-chemotherapy sP-selectin levels were highest in women who had received epirubicin, cytoxan, 5-fluorouracil chemotherapy (p < or = 0.01). These findings indicate that chemotherapy treatment can be associated with elevations in certain markers of inflammation, particularly markers of endothelial and platelet activation. Inflammation in response to chemotherapy is most significantly related to inflammation that existed prior to chemotherapy but also potentially to treatment regimen and to certain disease characteristics.
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Affiliation(s)
- Paul J Mills
- Department of Psychiatry, University of California, San Diego, CA 92103, USA.
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Patel KJ, Pambuccian SE, Ondrey FG, Adams GL, Gaffney PM. Genes associated with early development, apoptosis and cell cycle regulation define a gene expression profile of adenoid cystic carcinoma. Oral Oncol 2006; 42:994-1004. [PMID: 16762588 DOI: 10.1016/j.oraloncology.2005.12.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2005] [Revised: 12/08/2005] [Accepted: 12/12/2005] [Indexed: 10/24/2022]
Abstract
Adenoid cystic carcinoma (ACC) is an uncommon salivary gland malignancy characterized by indolent yet relentless growth that exhibits inherent resistance to systemic chemotherapy, surgical salvage and conventional radiotherapy. We used microarray analysis to characterize gene expression changes associated with ACC. Eight ACC patient specimens were compared with normal parotid gland tissue and the ACC3 cell line. Differentially expressed genes were identified (512 total) using supervised analysis methods and functional categories assigned using OntoExpress. Genes associated with morphogenesis, neurogenesis, proliferation and apoptosis characterized ACC tumors. Genes associated with saliva production and immune response characterized normal parotid tissues while the ACC3 cell line expressed genes primarily associated with proliferation, chromosome maintenance and the cell cycle. These results demonstrate that ACC tumors express genes associated with early developmental processes including morphogenesis and neurogenesis implicating oncogenic events that result in dedifferentiation of normal salivary glands.
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Affiliation(s)
- Ketan J Patel
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota School of Medicine, MMC 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA
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Lirdprapamongkol K, Sakurai H, Kawasaki N, Choo MK, Saitoh Y, Aozuka Y, Singhirunnusorn P, Ruchirawat S, Svasti J, Saiki I. Vanillin suppresses in vitro invasion and in vivo metastasis of mouse breast cancer cells. Eur J Pharm Sci 2005; 25:57-65. [PMID: 15854801 DOI: 10.1016/j.ejps.2005.01.015] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2004] [Revised: 12/22/2004] [Accepted: 01/24/2005] [Indexed: 11/29/2022]
Abstract
Vanillin, a food flavoring agent, has been reported to show anti-mutagenic activity and to inhibit chemical carcinogenesis. In this study, we examined the effect of vanillin on the growth and metastasis of 4T1 mammary adenocarcinoma cells in BALB/c mice. Mice orally administered with vanillin showed significantly reduced numbers of lung metastasized colonies compared to controls. In vitro studies revealed that vanillin, at concentrations that were not cytotoxic, inhibited invasion and migration of cancer cells and inhibited enzymatic activity of MMP-9 secreted by the cancer cells. Vanillin also showed growth inhibitory effect towards cancer cells in vitro. However, vanillic acid, a major metabolic product of vanillin in human and rat, was not active in these in vitro activity assays. Our findings suggest that vanillin has anti-metastatic potential by decreasing invasiveness of cancer cells. Since vanillin is generally regarded as safe, it may be of value in the development of anti-metastatic drugs for cancer treatment.
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Affiliation(s)
- Kriengsak Lirdprapamongkol
- Division of Pathogenic Biochemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
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7
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Alessandro R, Flugy AM, Russo D, Stassi G, De Leo A, Corrado C, Alaimo G, De Leo G. Identification and phenotypic characterization of a subpopulation of T84 human colon cancer cells, after selection on activated endothelial cells. J Cell Physiol 2005; 203:261-72. [PMID: 15484219 DOI: 10.1002/jcp.20236] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The extravasation of metastatic cells is regulated by molecular events involving the initial adhesion of tumor cells to the endothelium and subsequently the migration of the cells in the host connective tissue. The differences in metastatic ability could be attributed to properties intrinsic of the various primary tumor types. Thus, the clonal selection of neoplastic cells during cancer progression results in cells better equipped for survival and formation of colonies in secondary sites. A cell line (T84SF) exhibiting an altered phenotypic appearance was selected from a colon cancer cell line (T84) by repetitive plating on TNFalpha-activated human endothelial cells and subsequent selection for adherent cells. Cell growth, motility, chemoinvasive abilities, tyrosine phosphorylation signaling, and the metastasis formation in nude mice of the two cell lines was compared. T84SF cells displayed in vitro an higher proliferation rate and a more invasive behavior compared to the parental cells while formed in vivo a greater number of metastatic colonies in nude mice. As concerns the signaling underlying the phenotypes of the selected cells, we examined the general tyrosine phosphorylation levels in both cell lines. Our results indicate that T84SF have an increased basal tyrosine phosphorylation of several proteins among which src kinase was identified. Treatment of cells with a specific inhibitor of src activity caused a greater in vitro inhibition of proliferation and invasive properties of T84 parental cells with respect to T84SF cells and diminished metastasis formation in vivo. Altogether, these data provide evidences that this new cell line may be valuable for identifying molecular mechanisms involved in the metastatic progression of colon cancer.
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Affiliation(s)
- R Alessandro
- Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Palermo, Italy.
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Mills PJ, Parker B, Jones V, Adler KA, Perez CJ, Johnson S, Cohen-Zion M, Marler M, Sadler GR, Dimsdale JE, Ancoli-Israel S. The effects of standard anthracycline-based chemotherapy on soluble ICAM-1 and vascular endothelial growth factor levels in breast cancer. Clin Cancer Res 2005; 10:4998-5003. [PMID: 15297400 DOI: 10.1158/1078-0432.ccr-0734-04] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The circulating soluble form of intercellular adhesion molecule-1 (sICAM-1) and vascular endothelial growth factor (VEGF) are elevated in women with breast cancer and associated with tumor progression and poor prognosis. This study examined the effects of anthracycline-based chemotherapy on plasma sICAM-1 and VEGF, as well as soluble P-selectin, von Willebrand factor, and interleukin-6 levels. EXPERIMENTAL DESIGN Twenty-six women diagnosed with stage I-IIIA breast cancer (mean age, 48.4 +/- 10.4 years; range, 34-79 years) were studied before (week 1) and at weeks 2 and 3 of cycles 1 and 4 of chemotherapy. RESULTS The initial effect of chemotherapy was to reduce sICAM-1 levels; compared with pretreatment, sICAM-1 levels were decreased at week 2 of both cycles (P values < 0.01). sICAM-1 levels were elevated, however, at the start of cycle 4 as compared with pretreatment (P < 0.01). Chemotherapy led to an increase in sICAM-1 levels in node-positive but not node-negative patients (P < 0.01). VEGF levels were decreased at week 2 of cycle 4 (P = 0.001) and remained so at week 3. Similar to sICAM-1, VEGF levels were elevated at the start of cycle 4 as compared with pretreatment (P < 0.006). Soluble P-selectin levels decreased during week 2 of cycle 4 (P = 0.026). Neither interleukin-6 or von Willebrand factor were significantly changed in response to chemotherapy. CONCLUSIONS The findings support prior studies suggesting that sICAM-1 levels derive from sources other than endothelial cells. In addition, whereas the more immediate effect of chemotherapy is to reduce sICAM-1 and VEGF, continued treatment may lead to significant elevations.
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Affiliation(s)
- Paul J Mills
- Department of Psychiatry, University of California San Diego, San Diego, California 92103, USA.
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Mills PJ, Parker B, Dimsdale JE, Sadler GR, Ancoli-Israel S. The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer. Biol Psychol 2005; 69:85-96. [PMID: 15740827 DOI: 10.1016/j.biopsycho.2004.11.007] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Chemotherapy for breast cancer leads to increased fatigue, poor mood, and reduced quality of life. Few studies have examined possible changes in inflammation during chemotherapy as potential contributors to this phenomenon. This study examined the relationship among circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) and fatigue, depressed mood, and quality of life before and during anthracycline-based chemotherapy. Twenty-nine women diagnosed with stage I-IIIA breast cancer (mean age 49.5 years, S.D.+/-11) were studied prior to cycle 1 of chemotherapy and 2.5 months later at the start of cycle 4 of chemotherapy. Chemotherapy led to a significant increase in sICAM-1 (P<0.05) and VEGF (P<0.01) levels, as well as increased ratings of fatigue (P<0.01), depressed mood (P<0.03), and poorer quality of life (P<0.01). Multiple regression analyses revealed that elevated VEGF (P<0.01) and sICAM-1 (P<0.02) were related to the increased fatigue and/or poorer quality of life as a result of chemotherapy. Pre-chemotherapy levels of VEGF and pre-chemotherapy ratings of quality of life predicted quality of life in response to chemotherapy (P<0.001). The findings contribute to the literature by showing that both pre-chemotherapy and chemotherapy-induced changes in inflammation are related to changes in fatigue and quality of life in response to chemotherapy.
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Affiliation(s)
- Paul J Mills
- Department of Psychiatry, University of California, San Diego (UCSD), Medical Center, 200 West Arbor Drive, San Diego, CA 92103-0804, USA.
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Abstract
AIM: To investigate the pathogenic mechanism of colon cancer at the molecular level and to elucidate the relationship between intercellular adhesion molecule-1 (ICAM-1) and nm23H1 genes and Chinese patients with colon cancer.
METHODS: DNA was extracted from paraffin-embedded materials. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to analyze MSI and LOH. Expression of ICAM-1 was detected by Envision immuno-histochemistry. Experimental results were analyzed with Leica-Qwin computer imaging techniques and SPSS software of statistics.
RESULTS: ICAM-1 expression of lymphatic endothelium was negative in normal colon and positive in colon cancer respectively. The number of lymphatics positive for ICAM-1 was gradually increased with degree of cancer invasion (P < 0.01). In the group with metastasis of colon cancer, the number of lymphatics positive for ICAM-1 in lymph nodes was more than that in the group with no metastasis (P < 0.01). The frequency of MSI, LOH and nm23H1 protein was 26.67%, 20.00% and 53.33% in colon cancer, respectively. In TNM staging, MSI (43.75%) and nm23H1 protein (81.25%) in stages I + II were detected more easily than the corresponding indexes (MSI: 7.14%, P < 0.05 and nm23H1: 21.43%, P < 0.01) in stages III + IV. By comparison, the frequency of LOH (35.71%) in stages III + IV was more than that of LOH (6.25%, P < 0.05) in stages I + II. LOH exhibited a rising trend along with the Duke’s staging. nm23H1 protein in the group of tubular adenocarcinoma (60.00%) was higher expressed than that in the group of mucoid adenocarcinoma (20.00%) (P < 0.01), and exhibited a rising trend with the differentiation degrees of tubular adenocarcinoma. nm23H1 protein in MSI positive group was higher expressed (75%) than that in MSI negative group (45.45%, P < 0.05).
CONCLUSION: The expression of ICAM-1 in lymphatic vessels is beneficial to the judgement of the invasion and metastasis ability of colon cancer and the anti-tumor immunity function, and shows an important clinical significance in predicting lymphatic metastasis of colon cancer. MSI and LOH may separately control the development of sporadic colon cancer with different pathways. LOH mostly arises in the late period of sporadic colon cancer and endows a high aggressive and poor prognostic phenotype. By compassion, MSI may be an early period molecule marker for sporadic colon cancer, enhanced expression of nm23H1 protein can effectively inhibit colon cancer metastasis and improve prognosis of sporadic colon cancer patients.
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Affiliation(s)
- Zhi-Hong Su
- Department of Histology and Embryology, Zhejiang University Medical College, Hangzhou 310031, Zhejiang Province, China
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Abstract
Thyroid tumorigenesis and carcinogenesis accompany progressive loss of thyroid-specific differentiated functions. Some thyroid cancers are or become dedifferentiated, and they become refractory to efficacy-proven conventional therapies such as radioiodine ablation therapy and thyrotropin (TSH)-suppressive therapy. Redifferentiation therapy by either redifferentiating agents or gene transfer of differentiation-related genes may retard tumor growth and make tumors respond to conventional therapies.
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Affiliation(s)
- Jin-Woo Park
- Department of Surgery, College of Medicine, Chungbuk National University, San 62 Kaeshin-dong, Heungdok-gu, Cheongju, 361-763 South Korea
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Xu G, Zhang YL, Huang W. Relationship between plasma D-dimer levels and clinicopathologic parameters in resectable colorectal cancer patients. World J Gastroenterol 2004; 10:922-3. [PMID: 15040048 PMCID: PMC4727010 DOI: 10.3748/wjg.v10.i6.922] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To assess the clinical significance of the D-dimer levels and the relationship between plasma D-dimer levels and clinicopathologic parameters in operable colorectal cancer patients.
METHODS: The plasma levels of D-dimer were measured pre- and postoperatively in 35 patients with colorectal cancer, and 30 healthy subjects served as controls by the method of quantitative enzyme-linked immunosorbent assay (ELISA).
RESULTS: The mean preoperative plasma levels of D-dimer in the patients with colorectal cancer (1.06 ± 0.24 mg/L) were significantly higher than those of controls (0.33 ± 0.12 mg/L, P < 0.01). The D-dimer levels were remarkably elevated on the 1st day after operation (1.22 ± 0.55 mg/L, P < 0.01). On the 3rd day the level of D-dimer began to stepwise descend and on the 14th day nearly returned to control level. The preoperative levels of D-dimer were significantly correlated with the lymph node metastasis and Dukes stage but had no association with tumor location and the degree of differentiation. A stepwise increase in the mean D-dimer levels was found with increase of the tumor stage.
CONCLUSION: Hypercoagulation and higher fibrinolytic activities occur in patients with colorectal cancer. The operative trauma could enhance the fibrinolysis in the patients with colorectal cancer. The measurement of preoperative D-dimer levels is considered to be useful for predicting lymph node metastasis and stage of colorectal cancer.
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Affiliation(s)
- Gang Xu
- Institute of Gastroenterology, First Military Medical University, Guangzhou 510515, Guangdong Province, China.
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Kawasaki M, Maeda T, Hanasawa K, Ohkubo I, Tani T. Effect of His-Gly-Lys motif derived from domain 5 of high molecular weight kininogen on suppression of cancer metastasis both in vitro and in vivo. J Biol Chem 2003; 278:49301-7. [PMID: 14506238 DOI: 10.1074/jbc.m308790200] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
We have demonstrated previously that kinin-free high molecular weight kininogen, its domain 5 (D5H, Gly402-Lys502), and peptides derived from D5H inhibited vitronectin-mediated migration and invasion of cancer cells in vitro (Kamiyama, F., Maeda, T., Yamane, T., Li, Y. H., Ogikubo, O., Otsuka, T., and Ohkubo, I. (2001) Biochem. Biophys. Res. Commun. 288, 975-980). In this study, we found that the amino acid sequence His-Gly-Lys (HGK) in D5H is the core motif for inhibition of adhesion and invasion of MDA-MB-231 cells in vitro. P-5m (484GHGKHKNK491, Gly484-Lys491), an octapeptide including the HGK motif derived from D5H, and HGK, a tripeptide, inhibited both cell adhesion and invasion in vitro. However, an octapeptide designated P-5m (K487R), in which Lys487 was changed to Arg, did not inhibit either cell adhesion or invasion, and peptides HGR and HGG also had no inhibitory effect. Recombinant GST-D5H expressed in Escherichia coli had a stronger inhibitory effect on cell adhesion and invasion in vitro than did GST-D5H (K487R) in which Lys487 was changed to Arg. Furthermore, P-5m (Gly484-Lys491) peptide clearly suppressed lung metastasis in mice experimentally induced by using B16-F10 cells, but P-5m (G487R) had no effect. These data strongly indicate that both the HGK motif and lysine residue (Lys487) play essential roles in inhibition of cell adhesion and invasion in vitro and in prevention of metastasis of cancer cells in vivo. We tried to identify the HGK motif binding protein on the surface of cancer cells. A 95-kDa surface biotin-labeled membrane protein was specifically detached from GST-D5H by P-5 (His479-Lys493) peptide but not by P-1 (Gly402-Lys420) peptide originating from the N-terminal region of D5H.
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Affiliation(s)
- Masayasu Kawasaki
- Department of Surgery, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan
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Zheng N, Ye SL, Sun RX, Zhao Y, Tang ZY. Effects of cryopreservation and phenylacetate on biological characters of adherent LAK cells from patients with hepatocellular carcinoma. World J Gastroenterol 2002; 8:233-6. [PMID: 11925598 PMCID: PMC4658357 DOI: 10.3748/wjg.v8.i2.233] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To improve the preparation of adherent lymphokine-activated killer (A-LAK) cells and to study the effects of cryopreservation and phenylacetate (PA) on biological characters of A-LAK cells.
METHODS: A-LAK cells were obtained from peripheral blood mononuclear cells (PBMCs) of the patients with hepatocellular carcinoma (HCC) by using L-phenylalanine methyl ester (PME) to deplete immunosuppressive monocytes. Proliferative activity of SMMC7721 cell line after treatment with phenylacetate (PA) was observed. A-LAK cells were treated with the supernatant of SMMC7721 cells that had been pretreated with PA. The changes of proliferation, cytotoxicity and phenotype of A-LAK cells were investigated after cryopreservation.
RESULTS: The expansion of A-LAK cells (96.79 ± 69.10 folds on Day 14) was significantly higher than that of non-adherent LAK (NA-LAK) cells (22.77 ± 13.20) as well as conventional LAK cells (4.64 ± 0.91). PA significantly suppressed the growth of SMMC7721 cells, and the inhibitor ratio was 46%. The supernatant of cultured tumor cells intensively suppressed the proliferation and cytotoxicity of A-LAK cells, but the suppressive effect of the supernatant was previously decreased after treatment with PA. Impairments in proliferation and cytotoxicity of A-LAK cells immediately after thawing of cryopreservation and recovery after reincubation with IL-2 were observed. The cytotoxicity of thawed A-LAK cells on Day 5 was significantly higher than that of fresh A-LAK before freezing (54.8% ± 10.2% vs 40.5% ± 6.4%). No significant change in the percentage of lymphocyte subsets was identified in frozen A-LAK cells as compared with that in the fresh control cells.
CONCLUSION: A-LAK cells can be simply prepared by using PME, and showed a synergistic anti-tumor effect with the combination of PA. Cryopreservation can increase the immunoactivities of A-LAK cells from the patients with hepatocellular carcinoma.
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Affiliation(s)
- Ning Zheng
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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Zheng N, Ye SL, Sun RX, Zhao Y, Tang ZY. The effect of phenylacetate on the expansion and cytotoxic activity of adherent lak cells from patients with hepatocellular carcinoma. Chin J Cancer Res 2002. [DOI: 10.1007/s11670-002-0001-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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