scholarly journals Cutaneous Metastasis after Surgery, Injury, Lymphadenopathy, and Peritonitis: Possible Mechanisms

2019 ◽  
Vol 20 (13) ◽  
pp. 3286 ◽  
Author(s):  
Isao Otsuka
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Function ◽  
Checkpoint Inhibitors ◽  
The Elderly ◽  
Cytotoxic T Cell ◽  
Hematogenous Metastasis ◽  
Elderly Age ◽  
Umbilical Metastasis ◽  
Skin Metastases

Cutaneous metastases from internal malignancies are uncommon. Umbilical metastasis, also known as Sister Joseph nodule (SJN), develops in patients with carcinomatous peritonitis or superficial lymphadenopathy, while non-SJN skin metastases develop after surgery, injury, and lymphadenopathy. In this review, the possible mechanisms of skin metastases are discussed. SJNs develop by the contiguous or lymphatic spread of tumor cells. After surgery and injury, tumor cells spread by direct implantation or hematogenous metastasis, and after lymphadenopathy, they spread by extranodal extension. The inflammatory response occurring during wound healing is exploited by tumor cells and facilitates tumor growth. Macrophages are crucial drivers of tumor-promoting inflammation, which is a source of survival, growth and angiogenic factors. Angiogenesis is promoted by the vascular endothelial growth factor (VEGF), which also mediates tumor-associated immunodeficiency. In the subcutaneous tissues that surround metastatic lymph nodes, adipocytes promote tumor growth. In the elderly, age-associated immunosuppression may facilitate hematogenous metastasis. Anti-VEGF therapy affects recurrence patterns but at the same time, may increase the risk of skin metastases. Immune suppression associated with inflammation may play a key role in skin metastasis development. Thus, immune therapies, including immune checkpoint inhibitors reactivating cytotoxic T-cell function and inhibiting tumor-associated macrophage function, appear promising.

scholarly journals Next-Generation Immunotherapies to Improve Anticancer Immunity

2021 ◽  
Vol 11 ◽  
Author(s):  
Yaoyao Shi ◽  
Katarzyna Tomczak ◽  
June Li ◽  
Joshua K. Ochieng ◽  
Younghee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Cell Subset ◽  
Cytotoxic T Cell ◽  
Killer Cells

Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell–mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.

scholarly journals Role of Tissue Factor in Cancer

2009 ◽  
Vol 27 (29) ◽  
pp. 4834-4838 ◽  
Author(s):  
Raj S. Kasthuri ◽  
Mark B. Taubman ◽  
Nigel Mackman
Keyword(s):  
Tumor Growth ◽  
Tissue Factor ◽  
Tumor Cells ◽  
Factor Vii ◽  
Hematogenous Metastasis ◽  
Mouse Tumor ◽  
Transmembrane Glycoprotein ◽  
Novel Approach ◽  
Clotting Cascade ◽  
Tumor Growth And Metastasis

Tissue factor (TF) is a transmembrane glycoprotein that localizes the coagulation serine protease factor VII/VIIa (FVII/VIIa) to the cell surface. The primary function of TF is to activate the clotting cascade. The TF:FVIIa complex also activates cells by cleavage of a G-protein coupled receptor called protease-activated receptor 2 (PAR2). TF is expressed by tumor cells and contributes to a variety of pathologic processes, such as thrombosis, metastasis, tumor growth, and tumor angiogenesis. For instance, tumor cells release TF-positive procoagulant microparticles into the circulation and these may trigger venous thromboembolism in patients with cancer. TF on circulating tumor cells also leads to the coating of the cells with fibrin that traps them within the microvasculature and facilitates hematogenous metastasis. In addition, TF:FVIIa-dependent activation of PAR2 on tumor cells increases tumor growth via an undefined mechanism. One possibility is that PAR2-dependent signaling increases the expression of proangiogenic proteins. Other studies have reported that endothelial cells in the tumor vasculature express TF and this may enhance angiogenesis. These results suggest that inhibition of TF should reduce several pathologic pathways that increase tumor growth and metastasis. This would represent a novel approach to anticancer therapy. Initial studies using inhibitors of the TF:FVIIa complex in mouse tumor models have produced encouraging results. Nevertheless, additional studies are needed to determine if this strategy can be successfully translated to the treatment of cancer patients.

scholarly journals 254 NTX-1088, a potent anti-PVR Mab induces DNAM1-mediated antitumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A275-A275
Author(s):  
Anas Atieh ◽  
Akram Obiedat ◽  
Guy Cinamon ◽  
Tihana Lenac Rovis ◽  
Paola Kucan Brlic ◽  
...  
Keyword(s):  
T Cells ◽  
Synergistic Effect ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Growth Inhibition

BackgroundPoliovirus receptor (PVR, CD155) represents a resistance mechanism to approved immune checkpoint inhibitors (ICIs). It is a key regulator of immune activation, that modifies function through multiple mechanisms. Increased PVR expression levels on tumor cells have been associated with resistance to anti-PD-(L)1 therapy, while loss of PVR led to reduced tumor growth. Targeting PVR using mAbs offers an attractive therapeutic approach for patients with advanced cancer, who are not responding to other ICIs.NTX-1088 is a first-in-class, anti-PVR mAb developed for the treatment of solid tumors and will enter clinical trials early 2022. The antibody binds PVR with high affinity, blocks its interactions with TIGIT and CD96, preventing their inhibitory signaling. Moreover, NTX-1088 forte is manifested through its ability to block the critical interaction between PVR and DNAM1 (CD226). This blockade prevents internalization of DNAM1, restores its expression on the surface of immune cells and results in a robust antitumor activity.MethodsNTX-1088 was rigorously tested in vitro and in-vivo. Various cancer cell lines were incubated with immune effector cells from healthy human donors, in the presence of NTX-1088, alone and in combination with anti-PD-1 mAb (pembrolizumab).ResultsNTX-1088 significantly increased immune cell activation, as measured by IFNg release from activated polyclonal CD8+ T cells, induction of CD137 and killing of tumor cells. When tested in combination with pembrolizumab, NTX-1088 further increased all measured activation parameters, suggesting a potential synergistic effect. A synergistic effect was obtained when NTX-1088 was combined with the anti-CD112R mAb, NTX-2R13, superior to TIGIT-CD112R combinations. When compared to anti-TIGIT mAb (tiragolumab), NTX-1088 demonstrated clear superiority in activating T and NK cells as stand-alone agent. Furthermore NTX-1088 in combination with pembrolizumab, was superior to the combination of pembrolizumab with anti-TIGIT.Importantly, NTX-1088 was the only intervention that significantly restored DNAM1 levels, whereas DNAM1 blockade reduced the activity of NTX-1088 to levels comparable to that of anti-TIGIT mAb.Humanized murine models confirmed the above observations; NTX-1088 exhibited a robust tumor growth inhibition, accompanied by significantly higher prevalence of CD137+, DNAM1+, CD8+ T cells, compared to mice treated by other ICIs.ConclusionsThis is the first report of drug-induced DNAM1 restoration and immune activation. NTX-1088 shows, for the first time, exclusive triple mechanism of action, whereby simultaneous and effective blockade of TIGIT and CD96 is complemented by the efficient restoration of DNAM1. This is a step change in antitumor immune activation, which will be validated in the clinic starting early 2022.

Factor XIII Supports Metastatic Potential through a Mechanism Coupled to Natural Killer Cell Function.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1753-1753
Author(s):  
Joseph S. Palumbo ◽  
Kelley A. Barney ◽  
Elizabeth A. Williams ◽  
Maureen A. Shaw ◽  
Anjali Mishra ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Survival ◽  
Nk Cells ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Metastatic Potential ◽  
Wild Type ◽  
Tumor Cell Survival

Abstract Interplay between the hemostatic and innate immune systems appears to be an important determinant of tumor metastasis. Studies of mice with selected hemostatic and/or immunological deficits have been particularly revealing, and indicate that platelets and fibrinogen support metastatic potential in part by impeding the clearance of newly formed micrometastases by natural killer (NK) cells. A key step in the formation of stable platelet/fibrin thrombi is the fXIII-mediated cross-linking of fibrin matrices. In order to examine the role of fXIII in tumor dissemination in detail, we studied tumor growth and metastasis in gene-targeted mice lacking the catalytic fXIII-A subunit (fXIII−/−). Comparative analyses of experimental lung metastases in immunocompetent fXIII−/− and wild-type mice showed that elimination of fXIII diminished the metastatic potential of both Lewis lung carcinoma (LLC) and B16-BL6 melanoma cells 5- to 10-fold. Loss of fXIII activity also significantly diminished tumor cell metastatic potential in spontaneous metastasis assays in which lung and liver lesions were quantified ∼2 weeks after resection of primary subcutaneous tumors. These differences were not the result of any genotype-dependent difference in tumor growth, as tumors transplanted into the dorsal subcutis of fXIII−/− and control mice grew at similar rates. In order to determine if fXIII was coupled to metastasis by a mechanism linked to NK cell function, we compared the early fate/survival of radiolabeled LLC cells in cohorts of fXIII−/− and wild-type mice pretreated with either an anti-asialo GM1 antibody known to deplete NK cells or control Ig. Here, the residual radiolabel present within lungs, blood and abdominal organs was measured 30 minutes or 26 hours after injection. Neither loss of fXIII nor NK cells had any impact on the initial localization of tumor cells within the lungs. The majority of the inoculum (∼90%) was present in the lungs 30 minutes after intravenous inoculation, with only scant amounts present in the other organs evaluated, regardless of mouse genotype or antibody treatment. Twenty-six hours after injection, fXIII deficiency resulted in a significant diminution in the apparent number of tumor cells remaining in the lungs in mice with intact NK cells. However, in mice immunologically depleted of NK cells, fXIII ceased to be a determinant of early tumor cell survival. These analyses identify fXIII as a significant determinant of metastatic potential and indicate that at least one mechanism whereby fXIII increases metastatic success is by impeding NK cell-mediated clearance of tumor cells. Given that these findings closely parallel previous observations made in fibrinogen-deficient mice, an attractive but still unproven model is that fXIII-mediated stabilization of fibrin/platelet aggregates associated with newly-formed micrometastases increases tumor cell survival in large part by limiting NK cell function. These studies also suggest that therapeutic strategies directed at fXIII might be useful in limiting malignant disease.

scholarly journals Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3169
Author(s):  
Iosune Baraibar ◽  
Marta Roman ◽  
María Rodríguez-Remírez ◽  
Inés López ◽  
Anna Vilalta ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Lung Adenocarcinoma ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Tumor Infiltration

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.

scholarly journals Clinical implication of cellular vaccine in glioma: current advances and future prospects

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Yuanliang Yan ◽  
Shuangshuang Zeng ◽  
Zhicheng Gong ◽  
Zhijie Xu
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Malignant Gliomas ◽  
Cytotoxic T Cell ◽  
Cell Mediated Immunity ◽  
Therapeutic Effects ◽  
Autologous Tumor ◽  
Cytotoxic T Cell Responses

AbstractGliomas, especially glioblastomas, represent one of the most aggressive and difficult-to-treat human brain tumors. In the last few decades, clinical immunotherapy has been developed and has provided exceptional achievements in checkpoint inhibitors and vaccines for cancer treatment. Immunization with cellular vaccines has the advantage of containing specific antigens and acceptable safety to potentially improve cancer therapy. Based on T cells, dendritic cells (DC), tumor cells and natural killer cells, the safety and feasibility of cellular vaccines have been validated in clinical trials for glioma treatment. For TAA engineered T cells, therapy mainly uses chimeric antigen receptors (IL13Rα2, EGFRvIII and HER2) and DNA methylation-induced technology (CT antigen) to activate the immune response. Autologous dendritic cells/tumor antigen vaccine (ADCTA) pulsed with tumor lysate and peptides elicit antigen-specific and cytotoxic T cell responses in patients with malignant gliomas, while its pro-survival effect is biased. Vaccinations using autologous tumor cells modified with TAAs or fusion with fibroblast cells are characterized by both effective humoral and cell-mediated immunity. Even though few therapeutic effects have been observed, most of this therapy showed safety and feasibility, asking for larger cohort studies and better guidelines to optimize cellular vaccine efficiency in anti-glioma therapy.

Hubungan Sikap dan Karakteristik Pasangan Usia Subur (PUS) dengan Keikutsertaan dalam Program KB di Wilayah Kerja UPT Puskesmas Sungai Raya Kecamatan Sungai Raya Kabupaten Aceh Timur

2020 ◽  
Vol 8 (2) ◽  
pp. 105-114
Author(s):  
Ainul Mardhiah ◽  
Nova Hasbani Prima Dewi ◽  
Aminy Aminy
Keyword(s):  
Family Planning ◽  
Family Planning Program ◽  
The Elderly ◽  
P Value ◽  
Planning Program ◽  
Elderly Age ◽  
Chi Square ◽  
Cross Sectional ◽  
The Family ◽  
Relationship Of

The family planning program also aims to improve the quality of the family in order to generate a sense of security, peace and hope of a better future in realizing the prosperity of birth and inner happiness. Allegedly the factor causing EFA participation in the family planning program is characteristic. The purpose of this research is to know the relationship of attitude and characteristic of Elderly Age Couple (PUS) with participation in family planning program at UPT Puskesmas Sungai Raya Sungai Raya District, East Aceh regency 2018. The research design used was analytic survey with cross sectional design. The population of this study is all Pairs Age of Fertile located in Work Area UPT Sungai Raya Public Health Service Center in January to December 2017 which amounted to 1897 people. Sampling using Slovin formula, obtained as many as 95 samples. The study was conducted from 7-17 July 2018 using questionnaires by interview. Statistical test using chi-square test. Result of research indicate that majority of fertile couple couples (PUS) participate in family planning program as much as 67 respondents (70,5%). Statistically there is relationship of attitude and characteristic of Elderly Age Couple (EFA) with non participation in family planning program in Working Area of UPT Puskesmas Sungai Raya Sungai Raya District of East Aceh Regency 2018 with p value <0,1. It is recommended that the family planning program holders in UPT Puskesmas Sungai Raya Sungai Raya District of East Aceh District to invite cross-sectoral figures to hold meetings to create mini workshop plans at least once a month to increase the participation of the Elderly Age Couple (PUS) in family planning programs. Keyword : Family Planning Program, Attitudes, CharacteristicsABSTRAKProgram KB juga bertujuan untuk meningkatkan kualitas keluarga agar dapat timbul rasa aman, tentram, dan harapan masa depan yang lebih baik dalam mewujudkan kesejahteraan lahir dan kebahagiaan batin. Diduga faktor yang menyebabkan ketidakikutsertaan PUS dalam program KB adalah karakteristik. Tujuan penelitian ini untuk mengetahui hubungan sikap dan karakteristik Pasangan Usia Subur (PUS) dengan keikutsertaan dalam program KB di Wilayah Kerja UPT Puskesmas Sungai Raya Kecamatan Sungai Raya Kabupaten Aceh Timur tahun 2018. Desain penelitian yang digunakan adalah survei analitik dengan rancangan bedah lintang. Populasi dari penelitian ini adalah seluruh Pasangan Usia Subur yang berada di Wilayah Kerja UPT Puskesmas Sungai Raya pada bulan Januari sampai dengan Desember tahun 2017 yang berjumlah 1.897 orang. Pengambilan sampel menggunakan rumus Slovin, didapatkan sebanyak 95 sampel. Penelitian dilaksanakan dari tanggal 7-17 Juli tahun 2018 menggunakan kuesioner dengan cara wawancara. Uji statistik menggunakan uji chi-square. Hasil penelitian menunjukkan bahwa mayoritas Pasangan Usia Subur (PUS) ikut serta dalam program KB yaitu sebanyak 67 responden (70,5%). Secara statistik ada hubungan sikap dan karakteristik Pasangan Usia Subur (PUS) dengan ketidakikutsertaan dalam program KB di Wilayah Kerja UPT Puskesmas Sungai Raya Kecamatan Sungai Raya Kabupaten Aceh Timur tahun 2018 dengan p value < 0,1. Sebaiknya pemegang program KB di UPT Puskesmas Sungai Raya Kecamatan Sungai Raya Kabupaten Aceh Timur agar mengajak tokoh lintas sektor agar mengadakan pertemuan untuk membuat rencana loka karya mini setidaknya satu bulan sekali untuk meningkatkan keikutsertaan Pasangan Usia Subur (PUS) dalam program KB.Kata Kunci : Program KB, Sikap, Karakteristik

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

Sign in / Sign up

Export Citation Format

Share Document