Lipid droplets: could they be involved in cancer growth and cancer–microenvironment communications?

An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000661 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000661

Author(s):

Hui Wang ◽

Qian Xu ◽

Chanyuan Zhao ◽

Ziqi Zhu ◽

Xiaoqing Zhu ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Immune Evasion ◽

Essential Role ◽

Human Cancer ◽

Cancer Growth ◽

Cancer Tissue ◽

Cancer Microenvironment ◽

Antigen Specificity ◽

Immune Evasion Mechanism

BackgroundRecent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion.MethodsThe distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo.ResultsIn a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy.ConclusionThere appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.

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Ultrastructural Cytopiasmic Changes of Adrenal Cortex During Pregnancy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100063408 ◽

1969 ◽

Vol 27 ◽

pp. 298-299

Author(s):

T. M. Murad ◽

Karen Israel ◽

Jack C. Geer

Keyword(s):

Adrenal Gland ◽

Steroid Hormones ◽

Adrenal Cortex ◽

Lipid Droplets ◽

Plasma Cholesterol ◽

Adrenal Steroids ◽

Dynamic Changes ◽

Cortical Cells ◽

Acetyl Coenzyme A ◽

Adrenal Cortical Cells

Adrenal steroids are normally synthesized from acetyl coenzyme A via cholesterol. Cholesterol is also shown to enter the adrenal gland and to be localized in the lipid droplets of the adrenal cortical cells. Both pregnenolone and progesterone act as intermediates in the conversion of cholesterol into steroid hormones. During pregnancy an increased level of plasma cholesterol is known to be associated with an increase of the adrenal corticoid and progesterone. The present study is designed to demonstrate whether the adrenal cortical cells show any dynamic changes during pregnancy.

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Morphometric SEM study of the effects of ACTH on endothelial fenestrae in the rat adrenal cortex

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100111288 ◽

1984 ◽

Vol 42 ◽

pp. 234-235

Author(s):

J. Curtis ◽

K. S. Schwartz ◽

R. P. Apkarian

Keyword(s):

Anterior Pituitary ◽

Lipid Droplets ◽

Adrenocorticotropic Hormone ◽

Unit Area ◽

High Density Lipoproteins ◽

Capillary Endothelium ◽

Zona Fasciculata ◽

Sem Study ◽

Saline Vehicle ◽

Scanning Electron

A scanning electron microscope (SEM) study was made of the effect of adrenocorticotropic hormone (ACTH) on the size and numbers of fenestrae/unit area in the capillary endothelium of the zona fasciculata (ZF) of the rat adrenal. The stimulatory effect of ACTH on cholesterol uptake via high density lipoproteins in the rat and evidence for the secretion of glucocorticoids by exocytosis of lipid droplets described by Rhodin suggest that endothelial change may accompany these transport phenomena.Twelve rats received two Dexamethasone (DEX) ip injections (25 μg DEX/100 g body wt.), the first at 8 PM and the second at 8 AM the next day, to inhibit the release of endogenous ACTH by the anterior pituitary. The animals were then divided into two groups. Six animals received only saline vehicle and six rats received ACTH (100 ng/100 g body wt.).

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Polychlorinated biphenyl induced hepatocyte alterations

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010012789x ◽

1987 ◽

Vol 45 ◽

pp. 716-717

Author(s):

D.N. Collins ◽

J.N. Turner ◽

K.O. Brosch ◽

R.F. Seegal

Keyword(s):

Lipid Droplets ◽

Wistar Rats ◽

Homovanillic Acid ◽

Polychlorinated Biphenyl ◽

Corn Oil ◽

Environmental Pollutants ◽

Short Term ◽

Pcb Congeners ◽

Urinary Levels ◽

The Brain

Polychlorinated biphenyls (PCBs) are a ubiquitous class of environmental pollutants with toxic and hepatocellular effects, including accumulation of fat, proliferated smooth endoplasmic recticulum (SER), and concentric membrane arrays (CMAs) (1-3). The CMAs appear to be a membrane storage and degeneration organelle composed of a large number of concentric membrane layers usually surrounding one or more lipid droplets often with internalized membrane fragments (3). The present study documents liver alteration after a short term single dose exposure to PCBs with high chlorine content, and correlates them with reported animal weights and central nervous system (CNS) measures. In the brain PCB congeners were concentrated in particular regions (4) while catecholamine concentrations were decreased (4-6). Urinary levels of homovanillic acid a dopamine metabolite were evaluated (7).Wistar rats were gavaged with corn oil (6 controls), or with a 1:1 mixture of Aroclor 1254 and 1260 in corn oil at 500 or 1000 mg total PCB/kg (6 at each level).

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An ultrastructural study on the shark liver

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010016011x ◽

1990 ◽

Vol 48 (3) ◽

pp. 512-513

Author(s):

Masako Yamada ◽

Yutaka Tanuma

Keyword(s):

Portal Vein ◽

Kupffer Cells ◽

Ultrastructural Study ◽

Lipid Droplets ◽

Microscopic Level ◽

The Other ◽

Fish Stock ◽

Structural Studies ◽

Light Microscopic Level ◽

Perfusion Fixation

Although many fine structural studies on the vertebrate liver have been reported on mammals, avians, reptiles, amphibians, teleosts and cyclostomes, there are no studies on elasmobranchii liver except one by T. Ito etal. (1962) who studied it on light microscopic level. The purpose of the present study was to as certain the ultrastructural details and cytochemical characteristics of normal elasmobranchii liver and was to compare with the other higher vertebrate ones.Seventeen Scyliorhinus torazame, one kind of elasmobranchii, were obtained from the fish stock of the Ueno Zoo aquarium, Ueno, Tokyo. The sharks weighing about 300-600g were anesthetized with MS-222 (Sigma), and the livers were fixed by perfusion fixation via the portal vein according to the procedure of Y. Saito et al. (1980) for 10 min. Then the liver tissues were immersed in the same fixative for 2 hours and postfixed with 1% OsO4-solution in 0.1 Mc acodylate buffer for one hour. In order to make sure a phagocytic activity of Kupffer cells, latex particles (0.8 μm in diameter, 0.05mg/100 g b.w.) were injected through the portal vein for one min before fixation. For preservation of lipid droplets in the cytoplasm, a series of these procedure were performed under ice cold temperature until the end of dehydration.

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Where’s the fat? Freeze-fracture analysis of ingredient interactions in food systems

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100146084 ◽

1993 ◽

Vol 51 ◽

pp. 48-49

Author(s):

Jean Fincher

Keyword(s):

Lipid Droplets ◽

Food Systems ◽

Food Industry ◽

Freeze Fracture ◽

Food Science ◽

Complex Interactions ◽

Fat Reduction ◽

Important Trend ◽

Conventional Foods ◽

Whipped Cream

An important trend in the food industry today is reduction in the amount of fat in manufactured foods. Often fat reduction is accomplished by replacing part of the natural fat with carbohydrates which serve to bind water and increase viscosity. It is in understanding the roles of these two major components of food, fats and carbohydrates, that freeze-fracture is so important. It is well known that conventional fixation procedures are inadequate for many food products, in particular, foods with carbohydrates as a predominant structural feature. For some food science applications the advantages of freeze-fracture preparation procedures include not only the avoidance of chemical fixatives, but also the opportunity to control the temperature of the sample just prior to rapid freezing.In conventional foods freeze-fracture has been used most successfully in analysis of milk and milk products. Milk gels depend on interactions between lipid droplets and proteins. Whipped emulsions, either whipped cream or ice cream, involve complex interactions between lipid, protein, air cell surfaces, and added emulsifiers.

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Extracellular matrix: the gatekeeper of tumor angiogenesis

Biochemical Society Transactions ◽

10.1042/bst20190653 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1543-1555 ◽

Cited By ~ 10

Author(s):

Maurizio Mongiat ◽

Simone Buraschi ◽

Eva Andreuzzi ◽

Thomas Neill ◽

Renato V. Iozzo

Keyword(s):

Extracellular Matrix ◽

Tumor Angiogenesis ◽

Signaling Cascades ◽

Cancer Growth ◽

Cell Behavior ◽

Metastatic Progression ◽

Surface Receptors ◽

The Matrix ◽

Multiple Signaling

Abstract The extracellular matrix is a network of secreted macromolecules that provides a harmonious meshwork for the growth and homeostatic development of organisms. It conveys multiple signaling cascades affecting specific surface receptors that impact cell behavior. During cancer growth, this bioactive meshwork is remodeled and enriched in newly formed blood vessels, which provide nutrients and oxygen to the growing tumor cells. Remodeling of the tumor microenvironment leads to the formation of bioactive fragments that may have a distinct function from their parent molecules, and the balance among these factors directly influence cell viability and metastatic progression. Indeed, the matrix acts as a gatekeeper by regulating the access of cancer cells to nutrients. Here, we will critically evaluate the role of selected matrix constituents in regulating tumor angiogenesis and provide up-to-date information concerning their primary mechanisms of action.

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