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- apoptosis (7)
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- cell death (3)
- unfolded protein response (3)
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Proteins destined for the secretory pathway are processed in the endoplasmic reticulum (ER) where a delicate balance exists between protein folding and degradation of terminally misfolded proteins. Different physiological as well as pathological stress conditions however, can lead to an imbalance between the ER protein folding capacity and protein load, giving rise to an accumulation of misfolded proteins in the ER lumen, a condition dubbed as ‘ER stress’. In an attempt to meet the increased folding demand, cells utilize a conserved signaling pathway, the unfolded protein response (UPR), which is initially charged to re-establish ER homeostasis and support survival. If this mechanism fails, persistent ER stress will eventually cause this cytoprotective UPR to switch into a cell death pathway that can activate mitochondrial apoptosis. As such, the dual function of the UPR in controlling cell fate may play a part in disease development and response to stress signals in conflicting ways. The lethal arm of the UPR may contribute to pathologies that are linked to unscheduled cell death, like diabetes and certain neurodegenerative diseases such as Alzheimer's and Parkinson’s, or be utilized by certain anticancer drugs to kill cancer cells. On the other hand, activation of the pro-survival function of the UPR may assist processes like tumorigenesis and chemoresistance, by endowing cancer cells with an increased capability to adapt to their hostile environment and to cope with cellular damage. Therefore, a better understanding of the different signaling pathways that emanate from the stressed ER and how their integration modulates cell fate decisions represents a crucial requirement to develop new strategies aimed at targeting the UPR for therapeutic purposes.
Suprabasal BCL-2 Expression Does Not Sensitize to Chemically-induced Skin Cancer in Transgenic Mice
(2008)
Background: BCL-2 overexpression is frequently detected in nonmelanoma skin cancer. In normal skin, BCL-2 expression is restricted to the basal cell layer and the hair follicle bulge. Both contain stem cells targeted by carcinogens upon initiation of mouse skin carcinogenesis. It is unknown whether the anti-apoptotic activity of BCL-2 is involved in the susceptibility of this cell type to malignant transformation. If so, extending the pool of BCL-2-expressing cells to suprabasal skin layers should increase the likelihood of skin tumour formation. Materials and Methods: To resolve this issue, we generated a novel transgenic mouse line overexpressing BCL-2 in suprabasal layers of the epidermis. The influence of suprabasal BCL-2 on tumour formation was then tested by chemically inducing skin cancer using the two-stage initiation-promotion protocol. Results: Bcl-2 expression neither influenced the incidence nor the multiplicity of papillomas upon chemical tumour induction with 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradeca-noylphorbol-13-acetate (TPA), nor their progression to carcinomas. Conclusion: Suprabasal expression of BCL-2 in skin does not increase the formation of papillomas or their malignant progression to squamous cell carcinomas in two-stage mouse skin carcinogenesis.
Since its discovery in 1945, our knowledge of the structure and many functions of the endoplasmic reticulum (ER) has advanced at a phenomenal rate. Early studies focused on the structure, which was then followed by biochemical and functional studies associated with calcium storage and release from the ER, protein folding and secretion, ER associated degradation (ERAD) and ER stress responses. Currently there is a significant interest in the role of ER in such cellular processes as cell death, autophagy and cross-talk with other organelles. In this chapter we give an overview of the structural characteristics and biochemical functioning of the ER and describe its manifold roles in cellular physiology. Finally, we explain how the sensitive nature of the protein folding process in the ER enables this organelle to act as a sensor of a broad range of cellular stresses. Signals emanating from the stressed ER play central roles in differentiation processes, cellular homeostasis and cell death.
One of the early cellular responses to endoplasmic reticulum (ER) stress is the activation of the unfolded protein response (UPR). ER stress and the UPR are both implicated in numerous human diseases and pathologies. In spite of this, our knowledge of the molecular mechanisms that regulate cell fate following ER stress is limited. The UPR is initiated by three ER transmembrane receptors: PKR-like ER kinase (PERK), activating transcription factor (ATF) 6 and inositol-requiring enzyme 1 (IRE1). These proteins sense the accumulation of unfolded proteins and their activation triggers specific adaptive responses to resolve the stress. Intriguingly, the very same receptors can initiate signalling pathways that lead to apoptosis when the attempts to resolve the ER stress fail. In this review, we describe the known pro-apoptotic signalling pathways emanating from activated PERK, ATF6 and IRE1 and discuss how their signalling switches from an adaptive to a pro-apoptotic response.
BACKGROUND
Neuronal migration is a crucial process that allows neurons to reach their correct target location to allow the nervous system to function properly. AP-2alpha is a transcription factor essential for neural crest cell migration and its mutation results in apoptosis within this cell population, as demonstrated by genetic models.
RESULTS
We down-modulated AP-2alpha expression in GN-11 neurons by RNA interference and observe reduced neuron migration following the activation of a specific genetic programme including the Adhesion Related Kinase (Axl) gene. We prove that Axl is able to coordinate migration per se and by ChIP and promoter analysis we observe that its transcription is directly driven by AP-2alpha via the binding to one or more functional AP-2alpha binding sites present in its regulatory region. Analysis of migration in AP-2alpha null mouse embryo fibroblasts also reveals an essential role for AP-2alpha in cell movement via the activation of a distinct genetic programme.
CONCLUSION
We show that AP-2alpha plays an essential role in cell movement via the activation of cell-specific genetic programmes. Moreover, we demonstrate that the AP-2alpha regulated gene Axl is an essential player in GN-11 neuron migration.
Platelet-derived growth factors (PDGF) and their receptors control cell proliferation, survival, and migration. To test the influence of an oncogenic mutation to embryonic development, a transgenic mouse line expressing PDGFRalpha (D842V) was established and analyzed. Most of the embryos die on embryonic day 12.5 due to massive hemorrhages in the trunk. In mesenchymal cells of mutant animals, proliferation is decreased while apoptosis is increased. Further analyses reveal that the aortic blood vessels are enlarged showing a reduced numbers of vascular smooth muscle cells (vSMC) around the aorta. We hypothesize that the process of aortic wall formation is impaired, leading to subsequent rupture and leakage of the blood vessel resulting in death of the embryos. We speculate that misexpression of PDGFRalpha in SMCs causes failure of vSMC recruitment to the aorta.
Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.
Multiple myeloma is characterized by the malignant proliferating antibody-producing plasma cells in the bone marrow. Despite recent advances in therapy that improve the survival of patients, multiple myeloma remains incurable and therapy resistance is the major factor causing lethality. Clearly, more effective treatments are necessary. In recent years it has become apparent that, as highly secretory antibody-producing cells, multiple myeloma cells require an increased capacity to cope with unfolded proteins and are particularly sensitive to compounds targeting proteostasis such as proteasome inhibitors, which represent one of the most prominent new therapeutic strategies. Because of the increased requirement for dealing with secretory proteins within the endoplasmic reticulum, multiple myeloma cells are heavily reliant for survival on a set of signaling pathways, known as the unfolded protein response (UPR). Thus, directly targeting the UPR emerges as a new promising therapeutic strategy. Here, we provide an overview of the current understanding of the UPR signaling in cancer, and outline its important role in myeloma pathogenesis and treatment. We discuss new therapeutic approaches based on targeting the protein quality control machinery and particularly the IRE1α/XBP1 axis of the UPR.
In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies.
The development and growth of the skull is controlled by cranial sutures, which serve as growth centers for osteogenesis by providing a pool of osteoprogenitors. These osteoprogenitors undergo intramembranous ossification by direct differentiation into osteoblasts, which synthesize the components of the extracellular bone matrix. A dysregulation of osteoblast differentiation can lead to premature fusion of sutures, resulting in an abnormal skull shape, a disease called craniosynostosis. Although several genes could be linked to craniosynostosis, the mechanisms regulating cranial suture development remain largely elusive. We have established transgenic mice conditionally expressing an autoactivated platelet-derived growth factor receptor alpha (PDGFRalpha) in neural crest cells (NCCs) and their derivatives. In these mice, premature fusion of NCC-derived sutures occurred at early postnatal stages. In vivo and in vitro experiments demonstrated enhanced proliferation of osteoprogenitors and accelerated ossification of osteoblasts. Furthermore, in osteoblasts expressing the autoactivated receptor, we detected an upregulation of the phospholipase C-gamma (PLC-gamma) pathway. Treatment of differentiating osteoblasts with a PLC-gamma-specific inhibitor prevented the mineralization of synthesized bone matrix. Thus, we show for the first time that PDGFRalpha signaling stimulates osteogenesis of NCC-derived osteoblasts by activating the PLC-gamma pathway, suggesting an involvement of this pathway in the etiology of human craniosynostosis.
BACKGROUND
During pregnancy the mammary epithelium undergoes a complex developmental process which culminates in the generation of the milk-secreting epithelium. Secretory epithelial cells display lactogenic differentiation which is characterized by the expression of milk protein genes, such as beta-casein or whey acidic protein (WAP). Transcription factors AP-2alpha and AP-2gamma are downregulated during lactation, and their overexpression in transgenic mice impaired the secretory differentiation of the mammary epithelium, resulting in lactation failure. To explore whether the downregulation of AP-2alpha and AP-2gamma is of functional significance for lactogenic differentiation, we analyzed the expression of the AP-2 family members during the lactogenic differentiation of HC11 mammary epithelial cells in vitro. Differentiation of HC11 cells was induced following established protocols by applying the lactogenic hormones prolactin, dexamethasone and insulin.
FINDINGS
HC11 cells express all AP-2 family members except AP-2delta. Using RT-PCR we could not detect a downregulation of any of these genes during the lactogenic differentiation of HC11 cells in vitro. This finding was confirmed for AP-2alpha and AP-2gamma using Northern analysis. Differentiating HC11 cells displayed lower expression levels of milk protein genes than mammary glands of mid-pregnant or lactating mice.
CONCLUSION
The extent of lactogenic differentiation of HC11 cells in vitro is limited compared to mammary epithelium undergoing secretory differentiation in vivo. Downregulation of AP-2 transcription factor genes is not required for lactogenic differentiation of HC11 cells but may functionally be involved in aspects of lactogenic differentiation in vivo that are not reflected by the HC11 system.
Mouse mammary gland involution is associated with cytochrome c release and caspase activation
(2001)
At weaning, milk producing mammary epithelial cells undergo apoptosis and are removed by phagocytosis. Here, we show that mouse mammary gland involution is associated with mitochondrial cytochrome c release and processing of numerous caspases, including caspase-1, -3, -7, -8 and -9. Induction of caspase-3-like activity paralleled cleavage of poly-(ADP--ribose) polymerase. Dexamethasone inhibited processing of caspase-3, -7 and -8 and apoptosis, but had no effect on caspase-1 accumulation and cytochrome c release. In Bcl-2 transgenic animals, cytochrome c release, caspase activation and apoptosis were impaired. Thus, the pro-apoptotic signaling pathway in mammary epithelial cells during involution involves the release of cytochrome c and activation of caspases. It is inhibited by Bcl-2 at the mitochondrial level and by dexamethasone at a post-mitochondrial level.
After more than twenty years of research, the molecular events of apoptotic cell death can be succinctly stated; different pathways, activated by diverse signals, increase the activity of proteases called caspases that rapidly and irreversibly dismantle condemned cell by cleaving specific substrates. In this time the ideas that apoptosis protects us from tumourigenesis and that cancer chemotherapy works by inducing apoptosis also emerged. Currently, apoptosis research is shifting away from the intracellular events within the dying cell to focus on the effect of apoptotic cells on surrounding tissues. This is producing counterintuitive data showing that our understanding of the role of apoptosis in tumourigenesis and cancer therapy is too simple, with some interesting and provocative implications. Here, we will consider evidence supporting the idea that dying cells signal their presence to the surrounding tissue and, in doing so, elicit repair and regeneration that compensates for any loss of function caused by cell death. We will discuss evidence suggesting that cancer cell proliferation may be driven by inappropriate or corrupted tissue-repair programmes that are initiated by signals from apoptotic cells and show how this may dramatically modify how we view the role of apoptosis in both tumourigenesis and cancer therapy.
The differential extraction method is based on separate lysis of vaginal cells and spermatozoa and was designed to prevent mixed DNA profiles from intimate swabs. However, DNA from the victim can still be present in the sperm fraction, and the suspect’s DNA cannot be identified when only minute amounts of spermatozoa are present. Moreover, differential extraction is not effective when swabs contain sperms from more than one individual. Mixed profiles could ideally be overcome by analysing single spermatozoa. However, current multiplex STR kits are not yet sensitive enough to generate DNA profiles from single cells.
We have previously documented the cell-type-specific and hormone-dependent expression of the EphB4 receptor in the mouse mammary gland. To investigate its role in the biology of the mammary gland, we have established transgenic mice bearing the EphB4 receptor under the control of the MMTV-LTR promoter, which represents the first transgenic mouse model to investigate the effect(s) of unscheduled expression of EphB4 in adult organisms. Transgene expression in the mammary epithelium was induced at puberty, increased during pregnancy, culminated at early lactation and persisted until day three of post-lactational involution. In contrast, expression of the endogenous EphB4 gene is downregulated during pregnancy, is essentially absent during lactation and is re-induced after day three of post-lactational involution. The unscheduled expression of EphB4 led to a delayed development of the mammary epithelium at puberty and during pregnancy. During pregnancy, less lobules were formed, these however exhibited more numerous but smaller alveolar units. Transgenic mammary glands were characterized by a fragile, irregular morphology at lactation; however, sufficient functionality was maintained to nourish the young. Transgenic mammary glands exhibited untimely epithelial apoptotic cell death during pregnancy and abnormal epithelial DNA synthesis at early post-lactational involution, indicating a disturbed response to proliferative/apoptotic signals. Mammary tumours were not observed in the EphB4 transgenic animals; however, in double transgenic animals expressing both EphB4 and the neuT genes, tumour appearance was significantly accelerated and, in contrast to neuT-only animals, metastases were observed in the lung. These results implicate EphB4 in the regulation of tissue architecture, cellular growth response and establishment of the invasive phenotype in the adult mammary gland.
Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis
(1996)
Ductal morphogenesis in the rodent mammary gland is characterized by the rapid penetration of the stromal fat pad by the highly proliferative terminal endbud and subsequent formation of an arborized pattern of ducts. The role of apoptosis in ductal morphogenesis of the murine mammary gland and its potential regulatory mechanisms was investigated in this study. Significant apoptosis was observed in the body cells of the terminal endbud during the early stage of mammary ductal development. Apoptosis occurred predominately in defined zones of the terminal endbud; 14.5% of the cells within three cell layers of the lumen were undergoing apoptosis compared to 7.9% outside this boundary. Interestingly, DNA synthesis in the terminal endbud demonstrated a reciprocal pattern; 21.1% outside three cell layers and 13.8% within. Apoptosis was very low in the highly proliferative cap cell laver and in regions of active proliferation within the terminal endbud. In comparison to other stages of murine mammary gland development, the terminal endbud possesses the highest level of programmed cell death observed to date. These data suggest that apoptosis is an important mechanism in ductal morphogenesis. In p53-deficient mice, the level of apoptosis was reduced, but did not manifest a detectable change in ductal morphology, suggesting that p53-dependent apoptosis is not primarily involved in formation of the duct. Immunohistochemical examination of the expression of the apoptotic checkpoint proteins, Bcl-x, Bax and Bcl-2, demonstrated that they are expressed in the terminal endbud. Bcl-x and Bcl-2 expression is highest in the body cells and lowest in the nonapoptotic cap cells, implying that their expression is associated with increased apoptotic potential. Bax expression was distributed throughout the terminal endbud independent of the observed pattern of apoptosis. A functional role for Bcl-2 family members in regulating endbud apoptosis was demonstrated by the significantly reduced level of apoptosis observed in WAP-Bcl-2 transgenic mice. The pattern of apoptosis and ductal structure of endbuds in these mice was also disrupted. These data demonstrate that p53-independent apoptosis may play a critical role in the early development of the mammary gland.
Development of inducible genetic switches for in vivo use with transgenic mice has revolutionized many areas in modern molecular biology. Combining two techniques, Cre/loxP-based genetic recombination and ligand-dependent activation of a chimeric protein, we generated transgenic mice which allow for the spatiotemporal control of expression and of activity of the proto-oncogene c-myc. To these ends, the gene encoding the tamoxifen-inducible c-mycER(T) fusion protein (mycER(T)) was inserted in the ubiquitously active ROSA 26 gene locus by gene targeting. In the resulting ROSAMER allele, generalized transcription of the mycER(T) gene is prevented by a preceding transcriptional stop sequence which is flanked by loxP sites. Crosses of ROSAMER transgenic mice with Mox2 cre transgenic mice revealed tight control of mycER(T) transcription in various tissues unless the transcriptional stop sequence was removed by cre-mediated excision. Furthermore, we were able to demonstrate tamoxifen-dependent activation of the MycER(T) protein in embryonic fibroblasts derived from such mice. As a proof of principle, we demonstrate that primary neural crest cultures established from ROSAMER mice maintain their proliferative capacity in a 4-OHT-dependent manner. Furthermore, we demonstrate that such neural crest cells retain their differentiation potential as shown by expression of NF 160, a marker of neuronal differentiation upon 4-OHT withdrawal. The transgenic mice produced may thus be valuable tools for studying the cell type-specific effects of c-myc activity in development and disease.
AP-2 transcription factors play pivotal roles in orchestrating embryonic development by influencing the differentiation, proliferation, and survival of cells. Furthermore, AP-2 transcription factors have been implicated in carcinogenesis, a process where the normal growth and differentiation program of cells is disturbed. To experimentally address the potential involvement of AP-2 in mammary gland tumorigenesis, we generated mice overexpressing AP-2gamma by transgenesis using the mouse mammary tumor virus-long terminal repeat as the transgene-driving promoter unit. In the mammary gland, transgene expression elicited a hyperproliferation that, however, was counterbalanced by the enhanced apoptosis of epithelial cells leading to a hypoplasia of the alveolar epithelium during late pregnancy. In addition, secretory differentiation was impaired, resulting in a lactation failure. In male transgenic mice, the seminal vesicles were sites of strong transgene expression. There the effects of AP-2gamma on proliferation and apoptosis were even more pronounced, and differentiation was impaired, too, as revealed by the absence of androgen receptor immunoreactivity. In both tissues, the mammary gland and the seminal vesicles, enhanced steady-state transcript levels of the AP-2 target gene IGFBP-5 were detected, revealing a potential mechanism of AP-2-induced apoptosis. Our results suggest a role of AP-2 transcription factors in the maintenance of a proliferative and undifferentiated state of cells, characteristics not only important during embryonic development but also in tumorigenesis.
Bcl-2 is known to have dual antiproliferative and antiapoptotic roles. Overexpression of Bcl-2 in the mammary gland using a whey acidic protein (WAP) promoter-driven Bcl-2 transgene inhibits apoptosis in the mammary gland during pregnancy, lactation, and involution, and also counteracts apoptosis induced by overexpression of a mutant p53 transgene (WAP-p53 172 R-L). WAP-Bcl-2 mice and nontransgenic controls were treated with the carcinogen dimethylbenz(a)anthracene (DMBA). Surprisingly, the nontransgenic mice developed mammary tumors with decreased latency. Tumors arising in WAP-Bcl-2 mice displayed substantially reduced levels of proliferation relative to those seen in nontransgenic mice (P < 0.015), perhaps resulting in the observed increase in tumor latency following carcinogen treatment. This WAP-Bcl-2 mouse tumor model reflects the situation seen in some human breast cancers overexpressing Bcl-2, where expression of Bcl-2 has been shown to correlate with a lower proliferative index in tumors.
Gain of Bcl-2 is more potent than bax loss in regulating mammary epithelial cell survival in vivo
(1999)
The impact of gain of Bcl-2 function on mammary epithelial cell survival was compared with loss of Bax function during the two stages of mammary gland involution. Bcl-2 gain of function reduced apoptosis 50% during the first stage and increased cell survival 70% during the second stage. Complete loss of Bax reduced apoptosis by 20% during the first stage without second stage effect. Partial loss of Bax was ineffective but increased cell survival 2.4-fold when combined with Bcl-2 gain. Gain of Bcl-2 function is more potent than loss of Bax function in regulating mammary epithelial cell survival in vivo.
BACKGROUND
Activator protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2alpha and AP-2gamma is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo- or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms.
METHODS
We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant.
RESULTS
We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo- and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed Cell Death and Cell Adhesion and Migration as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo- and radiation therapy, (i.e. Ctgf, Nrp1, Tnfaip3, Gsta3) and AP-2 and other main apoptosis players and to create a unique network.
CONCLUSIONS
Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo- and radiation-resistance of tumor cells by impairing the ability to induce apoptosis. Therefore, interference with AP-2 function could increase the sensitivity of tumor cells towards therapeutic intervention.
One function ascribed to apoptosis is the suicidal destruction of potentially harmful cells, such as cancerous cells. Hence, their growth depends on evasion of apoptosis, which is considered as one of the hallmarks of cancer. Apoptosis is ultimately carried out by the sequential activation of initiator and executioner caspases, which constitute a family of intracellular proteases involved in dismantling the cell in an ordered fashion. In cancer, therefore, one would anticipate caspases to be frequently rendered inactive, either by gene silencing or by somatic mutations. From clinical data, however, there is little evidence that caspase genes are impaired in cancer. Executioner caspases have only rarely been found mutated or silenced, and also initiator caspases are only affected in particular types of cancer. There is experimental evidence from transgenic mice that certain initiator caspases, such as caspase-8 and -2, might act as tumor suppressors. Loss of the initiator caspase of the intrinsic apoptotic pathway, caspase-9, however, did not promote cellular transformation. These data seem to question a general tumor-suppressive role of caspases. We discuss several possible ways how tumor cells might evade the need for alterations of caspase genes. First, alternative splicing in tumor cells might generate caspase variants that counteract apoptosis. Second, in tumor cells caspases might be kept in check by cellular caspase inhibitors such as c-FLIP or XIAP. Third, pathways upstream of caspase activation might be disrupted in tumor cells. Finally, caspase-independent cell death mechanisms might abrogate the selection pressure for caspase inactivation during tumor development. These scenarios, however, are hardly compatible with the considerable frequency of spontaneous apoptosis occurring in several cancer types. Therefore, alternative concepts might come into play, such as compensatory proliferation. Herein, apoptosis and/or non-apoptotic functions of caspases may even promote tumor development. Moreover, experimental evidence suggests that caspases might play non-apoptotic roles in processes that are crucial for tumorigenesis, such as cell proliferation, migration, or invasion. We thus propose a model wherein caspases are preserved in tumor cells due to their functional contributions to development and progression of tumors.
Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in several different human cancers including breast. Gain of Bcl-2 function in mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model of breast cancer progression to determine its effect on epithelial cell survival and proliferation at three key stages in oncogenesis: the initial proliferative process, hyperplasia, and cancer. During the initial proliferative process, Bcl-2 strongly inhibited both apoptosis and mitotic activity. However as tumorigenesis progressed to hyperplasia and adenocarcinoma, the inhibitory effects on mitotic activity were lost. In contrast, anti-apoptotic activity persisted in both hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate during cancer progression. In this model, retention of anti-apoptotic activity with loss of anti-proliferative action resulted in earlier tumor presentation.
Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in several different human cancers including breast. Gain of Bcl-2 function in mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model of breast cancer progression to determine its effect on epithelial cell survival and proliferation at three key stages in oncogenesis: the initial proliferative process, hyperplasia, and cancer. During the initial proliferative process, Bcl-2 strongly inhibited both apoptosis and mitotic activity. However as tumorigenesis progressed to hyperplasia and adenocarcinoma, the inhibitory effects on mitotic activity were lost. In contrast, anti-apoptotic activity persisted in both hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate during cancer progression. In this model, retention of anti-apoptotic activity with loss of anti-proliferative action resulted in earlier tumor presentation.
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Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in several different human cancers including breast. Gain of Bcl-2 function in mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model of breast cancer progression to determine its effect on epithelial cell survival and proliferation at three key stages in oncogenesis: the initial proliferative process, hyperplasia, and cancer. During the initial proliferative process, Bcl-2 strongly inhibited both apoptosis and mitotic activity. However as tumorigenesis progressed to hyperplasia and adenocarcinoma, the inhibitory effects on mitotic activity were lost. In contrast, anti-apoptotic activity persisted in both hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate during cancer progression. In this model, retention of anti-apoptotic activity with loss of anti-proliferative action resulted in earlier tumor presentation.
