scholarly journals Paradoxical Roles of Peritumoral Hepatic Stellate Cells in Liver Tumorigenesis in Mice: Retarding Tumor Growth and Promoting Tumor Dissemination

2021 ◽  
Author(s):  
Cheng Tian ◽  
Liyuan Li ◽  
Li Fan ◽  
Anthony Brown ◽  
Eric J. Norris ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Liver Tumor ◽  
Hepatic Stellate Cells ◽  
Mouse Liver ◽  
Tumor Development ◽  
Stellate Cells ◽  
Growth Suppression ◽  
Tumor Dissemination

ABSTRACTBackground and RationaleCancer is increasingly being viewed as an ecosystem in which tumor cells coevolve and cooperate with host cells. In liver cancer, extensive biological changes have been reported in parenchymal hepatocytes (HCs) and non-parenchymal cells (NPCs) in the peritumoral microenvironment (pTME). However, it remains controversial how individ ual pTME populations contribute to liver tumorigenesis. We aim to develop an efficient in vitro model system to dissect the intricate relationship between liver tumor and its surroundings.ResultsIn this study, we established three-dimensional spheroid cocultures of primary mouse liver cells. We show that spheroids of HCs and NPCs can be readily generated in micropatterned multiwell plates. When cocultured with liver tumor spheroids, NPC spheroids, but not HC spheroids, exhibited a potent suppression activity on tumor cell growth. However, tumor cells (T) in NPC-T culture, while enduring growth suppression, showed a significant increase in dissemination compared to that in HC-T or T-alone culture. We then showed that hepatic stellate cells (HSCs) in NPCs are a key contributor to this NPC-mediated tumor growth suppression and dissemination augmentation. We validated our results in a highly metastatic orthotopic liver cancer allograft model. We showed that tumor development in this model induced widespread activation of HSCs in the pTME, and the accumulation of peritumoral HSCs at the tumor border is associated with retarded tumor growth and enhanced tumor dissemination.ConclusionThis study reveals a paradoxical role of peritumoral HSCs in liver tumorigenesis beyond being simply pro- or anti-tumorigenic. Tumor development in mouse liver induces activation of peritumoral HSCs that effectively retard tumor growth but simultaneously promote tumor dissemination.

Microfluidic co-culture of liver tumor spheroids with stellate cells for the investigation of drug resistance and intercellular interactions

The Analyst ◽  
2019 ◽  
Vol 144 (14) ◽  
pp. 4233-4240 ◽  
Author(s):  
Yuqing Chen ◽  
Wei Sun ◽  
Lu Kang ◽  
Yuerong Wang ◽  
Min Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Liver Cancer ◽  
Cancer Progression ◽  
Liver Tumor ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Tumor Spheroids ◽  
Intercellular Interactions

Hepatic stellate cells (HSCs), a major component of the tumor microenvironment in liver cancer, play important roles in cancer progression as well as drug resistance.

Latency-associated Peptide Degradation Fragments Produced in Stellate Cells and Phagocytosed by Macrophages in Bile Duct-ligated Mouse Liver

2021 ◽  
pp. 002215542110536
Author(s):  
Ikuyo Inoue ◽  
Xian-Yang Qin ◽  
Takahiro Masaki ◽  
Yoshihiro Mezaki ◽  
Tomokazu Matsuura ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Mouse Liver ◽  
Transforming Growth Factor ◽  
Degradation Products ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Early Stages ◽  
Cell Source

Transforming growth factor-β (TGF-β) activation is involved in various pathogeneses, such as fibrosis and malignancy. We previously showed that TGF-β was activated by serine protease plasma kallikrein-dependent digestion of latency-associated peptides (LAPs) and developed a method to detect LAP degradation products (LAP-DPs) in the liver and blood using specific monoclonal antibodies. Clinical studies have revealed that blood LAP-DPs are formed in the early stages of liver fibrosis. This study aimed to identify the cell source of LAP-DP formation during liver fibrosis. The N-terminals of LAP-DPs ending at residue Arg58 (R58) were stained in liver sections of a bile duct-ligated liver fibrosis model at 3 and 13 days. R58 LAP-DPs were detected in quiescent hepatic stellate cells at day 3 and in macrophages on day 13 after ligation of the bile duct. We then performed a detailed analysis of the axial localization of R58 signals in a single macrophage, visualized the cell membrane with the anti-CLEC4F antibody, and found R58 LAP-DPs surrounded by the membrane in phagocytosed debris that appeared to be dead cells. These findings suggest that in the early stages of liver fibrosis, TGF-β is activated on the membrane of stellate cells, and then the cells are phagocytosed after cell death: (J Histochem Cytochem XX:XXX–XXX, XXXX)

scholarly journals Strategies to Interfere with Tumor Metabolism through the Interplay of Innate and Adaptive Immunity

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 445 ◽  
Author(s):  
Javier Mora ◽  
Christina Mertens ◽  
Julia K. Meier ◽  
Dominik C. Fuhrmann ◽  
Bernhard Brüne ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Development ◽  
Metabolic Activation ◽  
Growth And Survival ◽  
Metabolic Characteristics ◽  
Inflammatory Phenotype ◽  
Tumor Outgrowth

The inflammatory tumor microenvironment is an important regulator of carcinogenesis. Tumor-infiltrating immune cells promote each step of tumor development, exerting crucial functions from initiation, early neovascularization, to metastasis. During tumor outgrowth, tumor-associated immune cells, including myeloid cells and lymphocytes, acquire a tumor-supportive, anti-inflammatory phenotype due to their interaction with tumor cells. Microenvironmental cues such as inflammation and hypoxia are mainly responsible for creating a tumor-supportive niche. Moreover, it is becoming apparent that the availability of iron within the tumor not only affects tumor growth and survival, but also the polarization of infiltrating immune cells. The interaction of tumor cells and infiltrating immune cells is multifaceted and complex, finally leading to different activation phenotypes of infiltrating immune cells regarding their functional heterogeneity and plasticity. In recent years, it was discovered that these phenotypes are mainly implicated in defining tumor outcome. Here, we discuss the role of the metabolic activation of both tumor cells and infiltrating immune cells in order to adapt their metabolism during tumor growth. Additionally, we address the role of iron availability and the hypoxic conditioning of the tumor with regard to tumor growth and we describe the relevance of therapeutic strategies to target such metabolic characteristics.

Changes in cytokine production and morphology of murine lymphoma NK/Ly cells in course of tumor development

2007 ◽  
Vol 2 (1) ◽  
pp. 71-86 ◽  
Author(s):  
Rostyslav Panchuk ◽  
Natalia Boiko ◽  
Maxim Lootsik ◽  
Rostyslav Stoika
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Ascitic Fluid ◽  
Tumor Development ◽  
Pcr Analysis ◽  
Vegf Mrna ◽  
Lymphoma Cells ◽  
Extracellular Medium ◽  
Enhanced Production ◽  
Ifn Γ

AbstractThe main goal of this study was to evaluate if specific cytokine expression in the NK/Ly lymphoma cells might be involved in development of intoxication in the tumor-bearing animals. RT-PCR analysis was used to study an expression of mRNA coding for IL-1α, IL-6, TNF-α, TNF-β and VEGF. ELISA was used to evaluate IL-6 and IFN-γ concentration in the ascitic fluid. Cytomorphological investigation of tumor cells was done after standard Romanovsky-Giemsa staining, and chromatin staining was performed with hematoxyline and neutral red. Lactate dehydrogenase and acid phosphatase release from tumor cells was estimated. It was revealed that the level of mRNA coding for VEGF and IL-6 was significant in the lymphoma cells. The level of VEGF mRNA was initially high and did not change during tumor progression, while the level of expression of IL6 mRNA was low at the initial stages of tumor growth and markedly increased (up to 5-fold) at the terminal stages. The obtained data on IL-6 mRNA expression were confirmed by ELISA, which showed more than 6-fold increase (from 90 to 570 pg/ml) in the IL-6 concentration in the ascitic fluid at late stages of NK/Ly tumor development. On the contrary to IL-6, concentration of IFN-γ in the ascitic fluid was very high at early stages of tumor development (1,000 pg/ml) and it markedly decreased (up to 30-fold, 30 pg/ml) at the terminal stages of tumor development. The high levels of IL-6 mRNA in tumor cells and IL-6 content in extracellular medium correlated with cell deterioration, as revealed by cytomorphologic study and the release of intracellular enzymes into extracellular medium. We suggest that an enhanced production and release of IL-6 by lymphoma cells can cause intoxication and exhaustion of the organism observed at terminal stages of tumor growth.

Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3302-3309 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Keith W. Kombrinck ◽  
Angela F. Drew ◽  
Timothy S. Grimes ◽  
John H. Kiser ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Potential ◽  
Thrombin Inhibitor ◽  
Tumor Dissemination ◽  
Hemostatic Factors ◽  
The Impact ◽  
Deficient Mice

Abstract Detailed studies of tumor cell–associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis.

Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3302-3309 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Keith W. Kombrinck ◽  
Angela F. Drew ◽  
Timothy S. Grimes ◽  
John H. Kiser ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Potential ◽  
Thrombin Inhibitor ◽  
Tumor Dissemination ◽  
Hemostatic Factors ◽  
The Impact ◽  
Deficient Mice

Detailed studies of tumor cell–associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis.

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