Apoptosis: Pathophysiology of Programmed Cell Death

doi:10.1016/S0344-0338(96)80089-6

Pathology - Research and Practice

Volume 192, Issue 7, 1996, Pages 676-683

https://doi.org/10.1016/S0344-0338(96)80089-6 Get rights and content

Summary

In all normal tissues, cell proliferation and cell death are balanced. The physiology of normal cell death, which has become generally known as apoptosis or programmed cell death, has been intensely investigated in recent years. In this review the cell biology and biochemistry of apoptosis are discussed. Although apoptosic cells can be morphologically recognized, characteristic molecular features such as internucleosomal DNA fragmentation, and histochemical techniques such as in situ end labeling, facilitate the recognition of apoptosis. Many of the genes involved in the regulation of apoptosis, which include cell growth associated genes such as c-myc and p53, have been identified. It has become clear that the bcl-genes (more explicitly bcl-2 and bax) are important apoptosis regulators. The details of the mechanism of programmed cell death are, however, not completely unraveled.

It has become clear that apoptosis plays an important role in organ and tissue development during embryogenesis. Examples are the morphogenesis of limbs from limb buds, the development of the central nervous system and the maturation of the hematopoietic and lymphatic systems. Hormonal regulation of cells and tissues is also partly executed through apoptosis. In a variety of diseases apoptosis plays a role. In cancer, apoptosis is a crucial feature, and in the resolution of inflammatory reactions, apoptosis is essential. In neurodegenerative diseases, dysregulation of the cell death programme may play a role. Further elucidation of the role of apoptosis in these diseases may lead to new possibilities for treatment.

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However, cellular forms of SFT tend to be less frequently positive for CD34; when positive, the staining is usually less strong than in fibrous SFT and often focal [5]. The function of bcl-2 oncoprotein is associated with the inhibition of apoptosis [30,31]. Some studies have reported that the expression of bcl-2 in SFT has no relation to whether the SFT is malignant or not [18,32,33].
Solitary fibrous tumor (SFT) is a rare neoplasm morphologically characterized by spindle cell proliferation. SFTs mostly arise from the pleura, but also involve a wide variety of the extrapleural organs. Especially, the development in the facial region is extremely rare. We describe an extremely rare case of SFT in the left preauricular region. The tumor lesion had gradually grown without pain or facial paralysis. Magnetic resonance imaging scan showed a circumscribed mass with high signal intensity on Gd-DTPA-enhanced T1-weighted images measuring approximately 3.0 cm in diameter. The tumor lesion was excised completely. Histological examination of the surgical specimen revealed proliferation of spindle tumor cells with a patternless pattern. Various amounts of collagen bundles intervened in the spindle tumor cells. The cellular atypia of the tumor cells was weak. Immunohistochemical studies showed strongly positive immunoreactivities for CD34, vimentin, and bcl-2. CD117 and STAT6 were also positive. The expression rates of nuclear staining for Ki-67 of the tumor cells were less than 1 %. Finally, a definitive diagnosis of SFT was made on the basis of the microscopic and immunohistochemical features. There was no recurrence or metastasis after surgical resection and the outcome was good. It is suggested that SFT should be included in the differential diagnoses for mesenchymal tumor of subcutaneous area adjacent to the parotid gland. We consider that a better understanding of the immunohistochemical profile of SFT in the facial subcutaneous region may play a useful role in making a definitive diagnosis.
Cigarette smoke condensate may disturb immune function with apoptotic cell death by impairing function of organelles in alveolar macrophages
2018, Toxicology in Vitro
Citation Excerpt :
Furthermore, cell debris can stimulate infiltration of surrounding immune cells as foreign materials (Bosman et al., 1996). Apoptotic cell death can be initiated by both intrinsic and extrinsic pathways, and the intrinsic pathway can be triggered by structural or functional damage of organelles (Elmore, 2007; Bosman et al., 1996). For instance, the endoplasmic reticulum (ER) houses intracellular stores of Ca2+, which acts as a second messenger in numerous physiological processes including protein synthesis, cell signaling, cell cycle regulation, metabolism, gene transcription, muscle contraction, and nerve conduction.
Considering that cigarette smoke condensate (CSC) is primarily absorbed through the alveoli in the lungs, herein, we used a mouse alveolar macrophage cell line (MH-S cells). After 24 h exposure, CSC decreased dose-dependently cell viability accompanying an increase in intracellular ROS and NO level. CSC structurally or functionally damaged organelles including mitochondria, ER and lysosome and enhanced the expression of proteins related to apoptosis, ER stress and DNA damage accompanying an elevated proportion of annexin V-bound cells. Meanwhile, the expression of certain proteins related to mitochondrial dynamics (OPA1 and DRP1) and autophagy (ATG5) did not overall show significant dose-dependent change in cells exposed to CSC. More importantly, conversion of LC3-I to LC3B-II, a representative marker for autophagy, was also unclear. Considering that intracellular organelles work together in harmony to perform defense mechanism against foreign bodies, we investigated changes in immune response following CSC exposure. The level of IFN-γ and MIP-1α was elevated in CSC-exposed cells, whereas the MCP-1α level decreased. The expression of chemokine receptors (CD195 and CXCR2) and an adhesion molecule (CD54) increased by CSC treatment, the expression of certain antigen presentation-related proteins (MHC class II, CD40, and CD80) were also enhanced. Meanwhile, the expression of CD86, a co-stimulatory molecule for antigen presentation, dose-dependently decreased. In conclusion, we suggest that CSC may induce apoptotic cell death and disturbance in host defense mechanisms by impairing function of cellular components.
The tumor antagonistic steroidal alkaloid Solanidine prompts the intrinsic suicidal signal mediated DFF-40 nuclear import and nucleosomal disruption
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Deregulation of this balance can add to either formation of the tumor or improper tissue loss through apoptosis. Being important regulatory mechanism in physiological and pathological conditions, better understanding of the regulatory mechanisms and targeting them for therapeutic approach through effective pharmacophore is upcoming strategy [38]. The strategy will effectively translate and selectively target deregulated signaling pathways in cancer cells which will pave the new path to bypass cancer cells treatment resistance [39].
Aim
Deformity in the cellular homeostatic event associated with cell survival and apoptosis are committing factors for carcinogenesis. Interventions of these events by pharmacologically active agent gain predominance in cancer treatment. In current investigation Solanidine, a steroidal alkaloid was evaluated on tumorigenesis by targeting death signal using multiple tumor cells and model systems.
Anti-proliferative effect was evaluated using cytotoxic studies. Prolonged cytotoxic effect of Solanidine was examined by colony formation assay. Exhibition of apoptotic hallmark induced by Solanidine was examined using FACS analysis, Annexin-V staining, Acridine orange staining, TUNEL assay. Altered gene expression was evaluated using Immunoblot, Immunofluorescence and Immunohistochemistry technique. In-vitro results were revalidated in EAC solid tumor and CAM xenograft model.
Solanidine exerts its potential effect in a target specific manner. The cytotoxic/anticlonogenic activity was due to induction of typical cellular apoptotic hallmarks and cell cycle blockage at S-G2/M phase. The molecular events underlying this effect is through activation of intrinsic pathway via Bax, Bad and Cytochrome c activation by neutralizing Bcl-2 expression, along with downregulated PI3K/Akt survival signal. As a consequence, downstream pro apoptogenic gene, active Caspase-3 was over expressed by Solanidine to cleave its substrate PARP and promotes nuclear import of DFF-40. Anti-carcinogenic aptitude was further confirmed by murine solid tumors and in-vivo CAM xenograft studies.
Solanidine emerged as active molecule against tomorigenesis by activating nuclear import of DFF-40 mediated nucleosomal disruption and cell demise. It can be developed as a potential apoptogenic small molecule for cancer therapy.
Morphologic Manifestations of Toxic Cell Injury
2013, Haschek and Rousseaux's Handbook of Toxicologic Pathology
Whatever causes injury to a cell – toxicant, toxin, infectious agent, or otherwise – the result is a simple or complex biochemical shift that generally results in a morphologic change which can be observed in some form. The pathologist must be able to recognize that such changes in morphology reflect a significant alteration in the cell’s homeostasis and then must decide whether or not this finding indicates reversible injury, irreversible injury, or adaptation to the new situation. Visible manifestations of disrupted function, whether ultrastructural, microscopic, or macroscopic, are lesions by definition, and lesions are still the primary means by which a toxicologic pathologist arrives at a diagnosis, hopefully one that includes the etiology as well as a description of the underlying morphologic alterations and a plausible pathogenesis of how the lesions came about. This chapter will serve as an overview of the basic histologic and ultrastructural features that reflect cell injury and cell death as well as the sequelae to such processes.
Morphologic Manifestations of Toxic Cell Injury
2013, Haschek and Rousseaux's Handbook of Toxicologic Pathology, Third Edition: Volume 1-3
Whatever causes injury to a cell – toxicant, toxin, infectious agent, or otherwise – the result is a simple or complex biochemical shift that generally results in a morphologic change which can be observed in some form. The pathologist must be able to recognize that such changes in morphology reflect a significant alteration in the cell’s homeostasis and then must decide whether or not this finding indicates reversible injury, irreversible injury, or adaptation to the new situation. Visible manifestations of disrupted function, whether ultrastructural, microscopic, or macroscopic, are lesions by definition, and lesions are still the primary means by which a toxicologic pathologist arrives at a diagnosis, hopefully one that includes the etiology as well as a description of the underlying morphologic alterations and a plausible pathogenesis of how the lesions came about. This chapter will serve as an overview of the basic histologic and ultrastructural features that reflect cell injury and cell death as well as the sequelae to such processes.
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¹: F. T. Bosman (Present Address), Department of Pathology, University of Lausanne, Rue du Bugnon 25, CH-1011 Lausanne, Switzerland

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Apoptosis: Pathophysiology of Programmed Cell Death

Summary

Neuron

elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell

Neuroscience

Curr Biol

Biochem Biophys Res Commun

Trends Neurosci

Curr Opin Neurobiol

Int Rev Cytol

elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell

The relation of programmed cell death to development and reproduction: comparative studies and an attempt at classification

Int Rev Cytol

Apoptotic cell death induced by c-myc is inhibited by bcl-2

Nature

Protection from Fasmediated apoptosis by a soluble form of the Fas molecule

Science

Fas and tumor necrosis factor receptor-mediated cell death: similarities and distinctions

J Exp Med

Apoptosis and programmed cell death in immunity

Annu Rev Immunol

Wild-type p53 mediates apoptosis by ElA, which is inhibited by ElB

Genes Dev

Mechanisms and functions of cell death

Annu Rev Cell Biol

Apoptosis: molecular mechanisms in programmed cell death

Eur J Cell Biol

Expression of Bcl-2 protein in hyperplastic polyps, adenomas and carcinomas of the colon

J Pathol

Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation

J Cell Biol

Immunocytochemical localization of BCL-2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy

Int J Cancer

Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice

Nature

Tetrazolium salt and electron-microscopic studies of cellular degeneration and necrosis in the interdigital areas of the developing chick limb

J Cell Sci

Caenorhabditis elegans gene ced-9 protects cells from programmed cell death

Nature

Mediation of c-Myc-induced apoptosis by p53

Science

BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death

Proc Natl Acad Sci USA

Molecular controls of apoptosis: differentiation/growth arrest primary response genes, proto-oncogenes, and tumor suppressor genes as positive & negative modulators

Oncogene

Bcl-2 protein in invasive ductal breast carcinomas

Virchows Arch

Cell proliferation markers and growth factors in ovarian cancer

Ann Med

Shrinkage necrosis: a distinct mode of cellular death

J Pathol

Definition and incidence of apoptosis: an historical perspective

Cell cycle and apoptosis: common pathways to life and death

J Cell Biochem

Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes

Proc Natl Acad Sci USA

Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene

Nature

Mechanism of antigen-driven selection in germinal centres

Nature

Apoptosis is induced by betaamyloid in cultured central nervous system neurons

Proc Natl Acad Sci USA