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Immunohistochemical evidence for an impairment of autophagy in tumorigenesis of gastric carcinoids and adenocarcinomas in rodent models and patients
Abstract
Background/aim:
Autophagy has dual roles in tumorigenesis: tumor-promoting or tumor-suppressing. The aim of the present study was to examine autophagy-related markers by immunohistochemistry in gastric carcinoids and adenocarcinomas in rodent models and patients.
Methods:
Gastric carcinoids in Mastomys were induced by loxtidine treatment. Spontaneously developed gastric adenocarcinomas in Japanese cotton rats and INS-GAS transgenic mice were included. Patient tissue samples of gastric carcinoids or adenocarcinomas were collected. Immunohistochemistry was performed against autophagy-related gene protein-6 (ATG-6, also called beclin-1), ATG-5 and ATG-16.
Results:
In tumor-free Mastomys, ATG-5, ATG-16 and beclin-1 were immunepositive in the gastric mucosa. In tumor-bearing Mastomys, ATG-5 and ATG-16 were negative in the tumors, whereas beclin-1 was positive in four of five animals. In carcinoid patients, ATG-5 was negative in six of ten, ATG-16 negative in nine of ten, and beclin-1 negative in three of ten patients. In cotton rats, ATG-5 and ATG-16 were negative in all tumors. Beclin-1 was negative in three of five rats. In INS-GAS mice, ATG-5 and beclin-1 were positive in the tumor area, but the numbers of immunopositive cells per gland were reduced by about 50% in comparison with wild-type mice. In adenocarcinoma patients, ATG-5 and ATG-16 were negative in eight of ten, and beclin-1 positive in all ten patients.
Conclusions:
An impaired autophagy took place at the stage of formation of ATG-5-ATG-12-ATG-16 complex in both gastric carcinoids and adenocarcinoma of both rodent models and patients. ATG-5 and ATG-16 might be better markers than beclin-1 in assessing autophagy in these lesions.
... Beclin 1 (mammalian homologue of yeast Atg6) and microtubuleassociated protein 1 light chain 3 (MAP1-LC3 or LC3, mammalian homologue of yeast Atg8) are involved in the biosynthesis of the autophagosome, which is the initial step of autophagy. Increased Beclin 1 [38][39][40] and LC3-I/ II conversion [39] was detected in human gastric cancer tissues. Upregulated Beclin 1 mRNA and protein is also noted in several gastric cancer cell lines, as compared with that in normal gastric mucosa cell line (GES-1) [41,42]. ...
... It should be noted that the protein expression of Atg5 is lost in 21.0% (21/100) of the gastric cancers [44]. In another study, Vigen et al. reported an extremely high negative expression of Atg5 and Atg16 in patients with gastric adenocarcinoma (Atg5, 80.0%, 8/10; Atg16, 80.0%, 8/10) or gastric carcinoid (Atg5, 60.0%, 6/10; Atg16, 90.0%, 9/10) [40]. Considering the number of samples is relatively small, further integrative work would be required by including considerably larger sample size. ...
... Absent in approximately one fifth of the gastric cancers [44], but is highly expressed in chemoresistant gastric cancer cells [72]. Associates with the shorter survival time in gastric cancer patients [72] Atg6/Beclin 1 A component of the class III PI3K complex that contributes to the biosynthesis of phagophore and autophagosomes [107] Upregulated in gastric cancer tissues [38][39][40] and several gastric cancer cell lines [41,42]. Increased Beclin 1 expression predicts a more favorable prognosis [41,95,96] Atg8/LC3 Involved in the cargo recruitment into, and the biosynthesis of autophagosomes [107] Upregulation of LC3 correlates Ki-67 in gastrointestinal cancers [99]. ...
Autophagy is a highly regulated catabolic pathway responsible for the degradation of long-lived proteins and damaged intracellular organelles. Perturbations in autophagy are found in gastric cancer. In host gastric cells, autophagy can be induced by Helicobacter pylori (or H. pylori) infection, which is associated with the oncogenesis of gastric cancer. In gastric cancer cells, autophagy has both pro-survival and pro-death functions in determining cell fate. Besides, autophagy modulates gastric cancer metastasis by affecting a wide range of pathological events, including extracellular matrix (ECM) degradation, epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, and tumor microenvironment. In addition, some of the autophagy-related proteins, such as Beclin 1, microtubule-associated protein 1 light chain 3 (MAP1-LC3), and p62/sequestosome 1 (SQSTM1) have certain prognostic values for gastric cancer. In this article, we review the recent studies regarding the functional role of autophagy in gastric cancer.
... The morbidity of gastric cancer is particularly high in China, where 23.9% of the total death toll resulting from tumors was attributed to patients with gastric cancer in 2012 (1). Although favorable therapeutic outcomes for the treatment of gastric cancer have been achieved by a combination of surgery and chemotherapy, distant metastasis and recurrence remain common in advanced stage patients (2,3). Progression of the tumor cells may be induced by a variety of factors, including multiple structural and functional genetic alterations, cell-cycle regulators, adhesion molecules and growth factors (2). ...
... Although favorable therapeutic outcomes for the treatment of gastric cancer have been achieved by a combination of surgery and chemotherapy, distant metastasis and recurrence remain common in advanced stage patients (2,3). Progression of the tumor cells may be induced by a variety of factors, including multiple structural and functional genetic alterations, cell-cycle regulators, adhesion molecules and growth factors (2). Study of these factors is of significant clinical value for further understanding the underlying molecular mechanisms of gastric cancer progression, as well as identifying novel therapeutic targets in gastric tissues (4)(5)(6). ...
... Beclin-1, the first identified mammalian autophagy effector, was reported to be deleted or significantly decreased in ovarian, breast and prostate cancer, suggesting that autophagy may be a tumor-suppressive mechanism (12). Notably, previous studies have indicated that low expression levels of Beclin-1 were predictive of poor survival in B cell lymphoma-xL-overexpressing hepatocellular carcinoma tissues (2,3). These observations indicate that autophagy has a significant role in tumorigenesis and prognosis. ...
Autophagy is a common phenomenon in cancer metabolism. However the mechanism and guiding significance of autophagy in the development of gastric cancer has remained to be elucidated. In the present study, 75 gastric cancer tissue specimens were collected at The China Japan Union Hospital of Jilin University (Changchun, China). Of these samples, 16 cases were stage 1, 40 stage 2 and 19 stage 3. Polymerase chain reaction and western blotting were used to detect the messenger RNA and protein expression of Beclin-1, a significant protein associated with cellular autophagy. It was found that expression of Beclin-1 in cancer tissues from stages 1 and 2 was higher, while in stage 3 cases levels were significantly lower than that of adjacent normal tissues. In addition, the infiltration of inflammatory cytokines was also increased in stage 1 and 2 cases. In vitro studies revealed that following stimulation with interferon-γ (IFN-γ), autophagy-associated proteins Beclin-1 and microtubule-associated protein light chain 3 were activated. Furthermore, activation of autophagy inhibited xenograft growth in nude mice. The results of these in vivo and in vitro experiments indicated that in gastric cancer tissues, autophagy was downregulated following the development of cancer tissue and that inflammation may be a significant factor in this process. IFN-γ may be involved in the mediation of this process and thus present a novel target for the treatment of gastric cancer.
... It has been reported that ATG2B, ATG5, ATG9B, ATG12, and ATG16L1 are closely related to gastric cancer (GC) [23]. The expressions of ATG5 and the ATG16L1 were downregulated in GC [26,27], and some ATG genes are also related to overall survival (OS) [23]. Furthermore, some genomic variations of ATG genes were reported as GC risk factors [25,28]. ...
... Vigen. R.A. et al. reported that ATG5 and ATG16L1 were negative in eight of ten adenocarcinoma patients, whereas they were positive all in normal tissue [26]. Furthermore, An. ...
Helicobacter pylori (H. pylori) infection causes a progression to atrophic gastritis and results in gastric cancer. Cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is injected into gastric epithelial cells using the type IV secretion system. On the other hand, gastric epithelial cells degrade CagA using an autophagy system, which is strictly regulated by the autophagy-related (ATG) genes. This study aimed to identify SNPs in ATG5, ATG10, ATG12, and ATG16L1 associated with gastric mucosal atrophy (GMA). Here, two-hundred H. pylori-positive participants without gastric cancer were included. The degree of GMA was evaluated via the pepsinogen method. Twenty-five SNPs located in the four candidate genes were selected as tag SNPs. The frequency of each SNP between the GMA and the non-GMA group was evaluated. The rs6431655, rs6431659, and rs4663136 in ATG16L1 and rs26537 in ATG12 were independently associated with GMA. Of these four SNPs, the G/G genotype of rs6431659 in ATG16L1 has the highest odd ratio (Odds ratio = 3.835, 95% confidence intervals = 1.337–1.005, p = 0.008). Further functional analyses and prospective analyses with a larger sample size are required.
... Several recent studies have indicated a role of autophagy and autophagy related proteins in the progression of gastric cancer [42,43]. Immunohistochemistry analysis Bar graphs (a, b, c, d and e) show mean +/− SEM (n = 3, P-value*: ≤ 0.05, ** ≤ 0.01, *** ≤ 0.001) has identified an elevated staining intensity for autophagy related proteins such as Beclin1, Atg5, Atg8/ MAP1LC3B, and SQSTM1/p62 in gastric cancer tissue [26,42]. ...
... Several recent studies have indicated a role of autophagy and autophagy related proteins in the progression of gastric cancer [42,43]. Immunohistochemistry analysis Bar graphs (a, b, c, d and e) show mean +/− SEM (n = 3, P-value*: ≤ 0.05, ** ≤ 0.01, *** ≤ 0.001) has identified an elevated staining intensity for autophagy related proteins such as Beclin1, Atg5, Atg8/ MAP1LC3B, and SQSTM1/p62 in gastric cancer tissue [26,42]. Upregulation of MAP1LC3A was shown to correlate with an increase in Ki67 positive cells in gastrointestinal tumors [44]. ...
Abstract
Background: The peptide hormone gastrin exerts a growth-promoting effect in both normal and malignant
gastrointestinal tissue. Gastrin mediates its effect via the cholecystokinin 2 receptor (CCKBR/CCK2R). Although a substantial part of the gastric adenocarcinomas express gastrin and CCKBR, the role of gastrin in tumor development is not completely understood. Autophagy has been implicated in mechanisms governing cytoprotection, tumor growth, and contributes to chemoresistance. This study explores the role of autophagy in response to gastrin in gastric adenocarcinoma cell lines.
Methods: Immunoblotting, survival assays and the xCELLigence system were used to study gastrin induced autophagy. Chemical inhibitors of autophagy were utilized to assess the role of this process in the regulation of cellular responses induced by gastrin. Further, knockdown studies using siRNA and immunoblotting were performed to explore the signaling pathways that activate autophagy in response to gastrin treatment.
Results: We demonstrate that gastrin increases the expression of the autophagy markers MAP1LC3B-II and SQSTM1 in gastric adenocarcinoma cells. Gastrin induces autophagy via activation of the STK11-PRKAA2-ULK1 and that this signaling pathway is involved in increased migration and cell survival. Furthermore, gastrin mediated increase in survival of cells treated with cisplatin is partially dependent on induced autophagy.
Conclusion: This study reveals a novel role of gastrin in the regulation of autophagy. It also opens up new avenues in the treatment of gastric cancer by targeting CCKBR mediated signaling and/or autophagy in combination with conventional cytostatic drugs.
Full article available: https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3055-5
... Some ATGs dysfunction may correlate with tumor progression and poorer patient survival. 2 Recently, researchers have paid more attention to the role of autophagy in the nervous system. Scientists reported that autophagic dysfunction is associated with neurodegenerative diseases such as Huntington's disease 3 and spinocerebellar ataxia, 4 which are associated with ineffective lysosomal clearance by autophagy. ...
Purpose:
Recent studies showed promotion of astrocyte autophagy in the spinal cord would provide analgesic effects. Silent information regulator T1 (SIRT1) and α subunit of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1α) are two master regulators of endogenous antioxidant defense and mitochondrial biogenesis. They play vital roles in both autophagy and neuropathic pain (NP). Our previous study showed that TSPO agonist Ro5-4864 elicited potent analgesic effects against NP, but the mechanisms remain unclear. This study aims to investigate the effects of TSPO agonist Ro5-4864 on autophagy and nuclear SIRT1/PGC-1α signaling in spinal dorsal horn.
Methods:
A rat model of L5 spinal nerve ligation (SNL) was adopted. Rats were randomly assigned to the Sham group, the SNL group, the Ro (TSPO agonist Ro5-4864) group and the Ro+3-MA group. The behavior assessments were conducted at baseline, on Day 1, 3, 7 and 14 after SNL. The autophagy-related proteins (ATG7, Beclin1, LC3, and P62) in spinal dorsal horn were assayed and the nuclear SIRT1/PGC-1α and downstream factors were analyzed.
Results:
Ro5-4864 alleviated the mechanical allodynia induced by SNL (P < 0.01 vs the SNL group), which could be totally abrogated by autophagy inhibitor 3-MA (P < 0.01 vs the Ro group). SNL induced elevated ATG7 (P < 0.01), Beclin1 (P < 0.01) and LC3-II/LC3-I (P < 0.01) contents and P62 accumulation (P < 0.01) on Day 7 and Day 14, which suggested an autophagy flux impairment. Ro5-4864 augmented ATG7 (P < 0.01), Beclin1 (P < 0.01) and LC3-II/LC3-I (P < 0.05) with decreased P62 (P < 0.01), which indicated a more fluent autophagic process. These effects were also totally abrogated by 3-MA (P < 0.01). Furthermore, Ro5-4864 activated the spinal nuclear SIRT1/PGC-1α signaling pathway.
Conclusion:
TSPO improved both autophagy impairment and mitochondrial biogenesis, which may provide a new strategy for the treatment of NP.
... Increased or attenuated expression of many ATGs is closely related to gastric carcinogenesis and the disturbances of GC cells' apoptosis. In many reports, such as the one of Vigen et al. for gastric adenocarcinomas, there is an increased expression of ATG16 (80% of GC cases) and ATG5 (80% of GC cases), while in cases of gastric carcinoid, the expression of ATG16 is higher (90%) in comparison with that of ATG5 (60%) [79]. ...
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis, and strategies for clinical management. However, many gastric tumors appear to be resistant to current chemotherapeutic agents. Moreover, a significant number of gastric cancer patients, with a lack of optimal treatment strategies, have reduced survival. In recent years, multiple research data have highlighted the importance of autophagy, an essential catabolic process of cytoplasmic component digestion, in cancer. The role of autophagy as a tumor suppressor or tumor promoter mechanism remains controversial. The multistep nature of the autophagy process offers a wide array of targetable points for designing novel chemotherapeutic strategies. The purpose of this review is to summarize the current knowledge regarding the interplay between gastric cancer development and the autophagy process and decipher the role of autophagy in this kind of cancer. A plethora of different agents that direct or indirect target autophagy may be a novel therapeutic approach for gastric cancer patients.
... Although M. natalensis rodents have been colonized and utilized as feeder rats for herpetologists, genetic analyses have shown these animals are M. coucha. While these animals have shown utility for certain cancer, autoimmune, and infectious disease models [6][7][8][9][10], their use in studying LASV dynamics remains minimal. ...
Mastomys natalensis are a ubiquitous and often dominant rodent across sub-Saharan Africa. Importantly, they are a natural reservoir for microbial pathogens including Lassa virus (LASV), the etiological agent of Lassa fever in humans. Lassa-infected rodents have been documented across West Africa and coincide with regions where annual outbreaks occur. Zoonotic transmission to humans most often occurs directly from infected rodents. Little is known about LASV infection kinetics and transmissibility in M.natalensis, primarily due to available animals. Here, we describe the establishment of a laboratory breeding colony of genetically confirmed M.natalensis from wild-captured rodents. This colony will provide a convenient source of animals to study LASV and other emerging pathogens that utilize M. natalensis in their enzootic lifecycles.
... Gastric cancer (GC) is the second most common human cancers worldwide and is di cult to be diagnosed in its early stage [1]. GC is extremely hard to be cured once it develops into metastasis stage [2,3]. Although the occurrence and progression of cancer are complex, numerous evidences indicate that aberrant intracellular Ca 2+ ([Ca 2+ ] i ) signaling is involved in the development of several types of gastrointestinal (GI) cancers, including GC and colon cancer [4]. ...
Background: Although the aberrant expression and function of most Ca²⁺-permeable channels are known to promote gastrointestinal tumors, the association of transient receptor potential vanilloid receptor 1(TRPV1) channels and gastric cancer (GC) has not been explored so far. We sought to determine their role in the development of GC and to elucidate the underlying molecular mechanisms.
Methods: The expression of TRPV1 in GC cells and tissues was detected by qPCR, immunohistochemistry, western blot analysis and immunofluorescence. CCK8 and flow cytometry were used to detect the proliferation and cell cycle, while transwell assay was used to detect migration and invasion. The role of TRPV1 in GC development in vivo was tested using tumor xenograft and peritoneal dissemination assays in nude mice.
Results: The decreased expression of TRPV1 protein in primary human GC tissues was closely correlated with poor prognosis of GC patients. TRPV1 protein was predominately expressed on the plasma membrane of several GC cell lines. TRPV1 overexpression attenuated proliferation, migration and invasion of GC cells in vitro, but TRPV1 knockdown increased them. Moreover, TRPV1 significantly reduced gastric tumor sizes, numbers and peritoneal dissemination in vivo. Mechanistically, TRPV1 overexpression increased [Ca²⁺]i, activated CaMKKβ and AMPK phosphorylation, and decreased expression of cyclin D1 and MMP2, but TRPV1 knockdown caused the opposite effects.
Conclusions: TRPV1 uniquely suppresses GC through a novel Ca²⁺/CaMKKβ/AMPK pathway and its downregulation is correlated with poor survival in human GC. TRPV1 upregulation and its downstream signaling may be a promising strategy for GC prevention and therapy.
... These ubiquitin inclusions may also correspond to inhibition of proteasomal degradation or to structural changes in the substrate proteins that hinder their degradation [16]. Apart from ubiquitin, several other marker proteins such as ULK1 [66], ATG5 [67,68], ATG7 [69], ATG12 [67], cathepsin D [24,65], LAMP1 [65,70], and beclin 1 [67,71] have previously been used to detect autophagy in tissue via immunohistochemistry. However, one caution is that a punctate staining pattern characteristic of autophagosome formation is rarely reported. ...
Autophagy is a highly conserved lysosomal degradation pathway with major impact on diverse human pathologies. Despite the development of different methodologies to detect autophagy both in vitro and in vivo, monitoring autophagy in tissue via immunohistochemical techniques is hampered due to the lack of biomarkers. Immunohistochemical detection of a punctate pattern of ATG8/MAP1LC3 proteins is currently the most frequently used approach to detect autophagy in situ, but it depends on a highly sensitive detection method and is prone to misinterpretation. Moreover, reliable MAP1LC3 immunohistochemical staining requires correct tissue processing and high-quality, isoform-specific antibodies. Immunohistochemical analysis of other autophagy-related protein targets such as SQSTM1, ubiquitin, ATG5 or lysosomal proteins is not recommended as marker for autophagic activity in tissue for multiple reasons including aspecific labeling of cellular structures and a lack of differential protein expression during autophagy initiation. To better understand the role of autophagy in human disease, novel biomarkers for visualization of the autophagic process with standard histology techniques are urgently needed.
... [6][7][8][9] The execution of autophagy involves a set of products, known as autophagy-related genes, and many autophagy genes have been found to be inactivated in human cancers. [10][11][12][13][14][15] Beclin1 is a mammalian autophagy gene which regulates autophagy by interacting with class III phosphatidylinositol-3-phosphate kinase (PI3KIII/Vps34). It participates in the early stages of autophagy by promoting nucleation of autophagic vesicles and recruiting proteins from the cytosol. ...
Mild hyperthermia enhances anti-cancer effects of chemotherapy, but the precise biochemical mechanisms involved are not clear. This study was carried out to investigate whether mild hyperthermia sensitizes gastric cancer cells to chemotherapy through reactive oxygen species–induced autophagic death. In total, 20 BABL/c mice of MKN-45 human gastric cancer tumor model were divided into hyperthermia + chemotherapy group, hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group. Reactive oxygen species production and expression of autophagy-related genes Beclin1, LC3B, and mammalian target of rapamycin were determined. The relationships between tumor growth regression, expression of autophagy-related genes, and reactive oxygen species production were evaluated. Tumor size and wet weight of hyperthermia + chemotherapy group was significantly decreased relative to values from hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group ( F = 6.92, p
... Very recently, the important role of the vagus nerve in gastric tumorigenesis has been investigated carefully in mouse models and in human patients [38]. Bilateral truncal vagotomy with pyloroplaty (VTPP) (Fig. 1) during the preneoplastic stage of tumorigenesis reduced the tumor incidence and size, and attenuated tumor cell proliferation specifically in the denervation portion of the stomach (after UVT) in the mouse models of gastric cancer, i.e., the genetically-induced mouse model (INS GAS) [39][40][41][42][43], a chemically-induced (MNU) mouse model and a Helicobacter pylori-infected mouse model [44]. More importantly, unilateral vagotomy (UVT) (Fig. 2), or local pharmacologic denervation via injection of botulinum toxin A in the gastric wall, similarly impaired preneoplastic growth, indicating the direct effect on tumor progression by vagus stimuli. ...
Vagotomy reduces gastric acid secretion and was therefore introduced as a surgical treatment for peptic ulcers in the 1970s. Later, it was replaced by acid reducing medication, such as histamine type 2 (H2) receptor antagonists and proton pump inhibitors (PPIs). A large body of evidence has indicated that drug-induced hypochlorhydriaper se does not increase the risk of gastric cancer. Early studies on the effects of vagotomy in chemically-induced rodent models of gastric cancer reported an increased risk of developing gastric cancer. This was most likely due to a delayed gastric emptying, which later has been accounted for by including an additional drainage procedure, e.g. pyloroplasty. In a recent study using three different mouse models of gastric cancer (including genetically engineered, chemically-induced and Helicobacter pylori-infected mice), either unilateral vagotomy or bilateral truncalvagotomy with pyloroplasty was found to significantly attenuate tumorigenesis in the denervated side of the stomach at early preneoplastic stages as well as at later stages of tumorigenesis. Consistently, pharmacological denervation using botulinum toxin A or muscarinic acetylcholine receptor 3 (M3R) blockade inhibited tumorigenesis. Moreover, it was found that recurrence of gastric cancer was reduced in patients following vagotomy. Thus, these new findings suggest the potential treatment strategies to target the nerve, neurotransmitters, corresponding receptors and their down-stream signaling pathways for the malignancy.
Complete blood count, serum chemistry values, and biological reference intervals were compared between two age groups (34-49 and 84-120 days old) of healthy male and female laboratory raised natal multimammate mice (Mastomys natalensis). Blood was collected via cardiocentesis under isoflurane anesthesia. Data sets of machine automated complete blood counts and clinical chemistries were analyzed. Significant differences between sex and age groups of the data sets were defined. The baseline hematologic and serum biochemistry values described here can improve interpretation of laboratory research using natal multimammate mice.
Background:
Coxsackievirus B3 (CVB3), a member of the picornavirus family, is one of the major causative enteroviruses of viral myocarditis. The aim of the current study was to investigate the role and underlying mechanism of iNOS and autophagy in CVB3 infected cardiomyocytes.
Methods:
Myocardial cell H9c2 were randomly divided into four groups: control group, CVB3 group, CVB3+L-NAME group and the CVB3+iNOS siRNA group. Cell proliferation was detected by MTT method and cell apoptosis was determined by flow cytometric. The protein expression levels were determined by Western blot. Anisomycin was used to activate JNK pathway in CVB3 infected H9c2 cells.
Results:
The results demonstrated that the inhibition of iNOS significantly elevated cell proliferation and suppressed cell apoptosis of CVB3-induced H9c2 cells. The production of MDA was obviously decreased, while the activity of SOD was increased by the addition of L-NAME or iNOS siRNA compared with the CVB3 group. Expression of the autophagy marker proteins LC3 II and Beclin 1 was significantly decreased, and the autophagy substrate p62 was dramatically increased in iNOS inhibition groups compared with the CVB3 group. Moreover, iNOS inhibition suppressed the JNK pathway in CVB3-infected H9c2 cells. Furthermore, administration of the JNK pathway stimulator, anisomycin, counteracted the effect of iNOS inhibition in CVB3-infected H9c2 cells.
Conclusion:
The inhibition of iNOS protects cardiomyocytes against CVB3-induced cell injury by regulating autophagy and the JNK pathway, which may provide a novel therapeutic strategy for treating CVB3-induced myocarditis.
Gastric cancer (GC) is one of the most frequent epithelial malignancies worldwide. The gastrointestinal (GI) peptide gastrin is an important regulator of the secretion and release of gastric acid from stomach parietal cells and it also plays a vital role in the development and progression of gastric cancer. The aim of the current study was to investigate the role and underlying mechanism of gastrin and autophagy in regulating gastric cancer tumorigenesis. Gastrin-17 amide (G-17) was applied in the gastric cancer cell lines SGC7901 and MGC-803. The results showed that G-17 maintained the high viability of SGC7901 and MGC-803. The expression of autophagy marker proteins LC3Ⅱand Beclin1 were significantly increased, while the autophagy substrate p62 was obviously decreased in the gastrin group compared with the control group. Moreover, G-17 strengthened the expressions of AMPKα, Ras, Raf, MEK and ERK1/2. Additionally, administration of AMPKα siRNA counteracted the effect of gastrin in SGC7901 cells. Finally, in an in vivo study of tumor growth and survival rate of rats, the levels of AMPKα/Ras/Raf/MEK/ERK were significantly increased in the gastrin group and decreased with following AMPKα shRNA injection. In conclusion, these findings indicate that gastrin plays a tumorigenic role by promoting autophagy in gastric cancer, and may provide a novel therapeutic target for gastric cancer treatment.
Mastomys rodents occupy a valuable niche in biomedical research, but there is very little published information regarding how to care for them in the laboratory. Here we provide information about the physical and behavioral characteristics of this unusual laboratory rodent, its taxonomic history, common diseases that affect it, and its use in research. We also provide housing recommendations based upon almost 15 years of experience successfully maintaining a colony of Mastomys coucha at our institution.
Beclin-1 has been identified as a reliable biomarker in monitoring the prognosis for tumors. We carried out a meta-analysis focusing on the relationship between beclin-1 and the clinical characteristics of patients with gastric cancer. We identified articles in MEDLINE, PubMed, Embase, ISI Web of Science, and Chinese National Knowledge Infrastructure databases by using the following strategy: ("beclin 1" or "beclin-1" or "ATG6") and ("gastric cancer" or "stomach cancer"). We conducted a final analysis of 1,254 patients from seven studies. The pooled odds ratio (OR) indicated a significant association between beclin-1 expression and the differentiation of gastric cancer (pooled OR = 0.23; 95 % confidence interval (CI) = 0.07-0.73) or tumor-node-metastasis staging of gastric cancer (pooled OR = 0.62; 95 % CI = 0.48-0.79). Beclin-1 expression was different in intestinal- and diffuse-type gastric cancer (pooled OR = 0.55; 95 % CI = 0.39-0.77). No association between beclin-1 and tumor size (pooled OR = 0.73; 95 % CI = 0.45-1.17) or lymph node metastasis (pooled OR = 0.59; 95 % CI = 0.17-1.99) was observed.
Gastric ECL-cell hyperplasia and carcinoids (ECLoma) develop after 1 year in rats treated with omeprazole or 2 months in Mastomys treated with loxtidine. The aim of this study was to examine the ultrastructure of ECL cells in Mastomys after loxtidine treatment with an attempt to evaluate whether an impairment of autophagy was involved in the tumorigenesis. Mastomys were given loxtidine for 8 or 27 weeks. Morphological analysis of ECL cells showed that (1) cell size was not increased after 8 or 27 weeks; (2) secretory vesicles, a hallmark feature of welldifferentiated ECL cells, were unchanged after 8 weeks but reduced after 27 weeks; (3) granules were reduced after 8 or 27 weeks; (4) microvesicles were unchanged after the treatment; and (5) vacuoles and lipofuscin bodies were found occasionally after 8 weeks but not at 27 weeks. In addition, the appearance of ECL-cell ultrastructure differed between loxtidine-treated Mastomys and rats treated with omeprazole or subjected to antrectomy, but was similar between Mastomys treated with loxtidine for 27 weeks and mice deficient in CCK(2) receptor. We suggest that the ultrastructure of ECL cells in Mastomys after long-term treatment with loxtidine displayed an impaired formation of vacuoles and lipofuscin bodies, markers of the autophagic pathway.
IFN-γ mediates responses to bacterial infection and autoimmune disease, but it is also an important tumor suppressor. It is upregulated in the gastric mucosa by chronic Helicobacter infection; however, whether it plays a positive or negative role in inflammation-associated gastric carcinogenesis is unexplored. To study this question, we generated an H(+)/K(+)-ATPase-IFN-γ transgenic mouse that overexpresses murine IFN-γ in the stomach mucosa. In contrast to the expected proinflammatory role during infection, we found that IFN-γ overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by interleukin-1beta (IL-1β) and/or Helicobacter infection. Helper T cell (Th) 1 and Th17 immune responses were inhibited by IFN-γ through Fas induction and apoptosis in CD4 T cells. IFN-γ also induced autophagy in gastric epithelial cells through increased expression of Beclin-1. Finally, in the gastric epithelium, IFN-γ also inhibited IL-1β- and Helicobacter-induced epithelial apoptosis, proliferation, and Dckl1(+) cell expansion. Taken together, our results suggest that IFN-γ coordinately inhibits bacterial infection and carcinogenesis in the gastric mucosa by suppressing putative gastric progenitor cell expansion and reducing epithelial cell apoptosis via induction of an autophagic program.
Autophagy is an evolutionarily conserved, catabolic process that involves the entrapment of cytoplasmic components within characteristic vesicles for their delivery to and degradation within lysosomes. Autophagy is regulated via a group of genes called AuTophaGy-related genes and is executed at basal levels in virtually all cells as a homeostatic mechanism for maintaining cellular integrity. The levels and cargos of autophagy can be modulated in response to a variety of intra- and extracellular cues to bring about specific and selective events. Autophagy is a multifaceted process and alterations in autophagic signalling pathways are frequently found in cancer and many other diseases. During tumour development and in cancer therapy, autophagy has paradoxically been reported to have roles in promoting both cell survival and cell death. In addition, autophagy has been reported to control other processes relevant to the aetiology of malignant disease, including oxidative stress, inflammation and both innate and acquired immunity. It is the aim of this review to describe the molecular basis and the signalling events that control autophagy in mammalian cells and to summarize the cellular functions that contribute to tumourigenesis when autophagy is perturbed.
A loss of stromal Cav-1 in the tumor fibroblast compartment is associated with early tumor recurrence, lymph-node metastasis, and tamoxifen-resistance, resulting in poor clincical outcome in breast cancer patients. Here, we have used Cav-1 (-/-) null mice as a pre-clinical model for this "lethal tumor micro-environment." Metabolic profiling of Cav-1 (-/-) mammary fat pads revealed the upregulation of numerous metabolites (nearly 100), indicative of a major catabolic phenotype. Our results are consistent with the induction of oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy. The two most prominent metabolites that emerged from this analysis were ADMA (asymmetric dimethyl arginine) and BHB (beta-hydroxybutyrate; a ketone body), which are markers of oxidative stress and mitochondrial dysfunction, respectively. Transcriptional profiling of Cav-1 (-/-) stromal cells and human tumor stroma from breast cancer patients directly supported an association with oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy, as well as ADMA and ketone production.
Autophagy is a catabolic membrane-trafficking process that leads to sequestration and degradation of intracellular material within lysosomes. It is executed at basal levels in every cell and promotes cellular homeostasis by regulating organelle and protein turnover. In response to various forms of cellular stress, however, the levels and cargoes of autophagy can be modulated. In nutrient-deprived states, for example, autophagy can be activated to degrade cargoes for cell-autonomous energy production to promote cell survival. In other contexts, in contrast, autophagy has been shown to contribute to cell death. Given these dual effects in regulating cell viability, it is no surprise that autophagy has implications in both the genesis and treatment of malignant disease. In this review, we provide a comprehensive appraisal of the way in which oncogenes and tumour suppressor genes regulate autophagy. In addition, we address the current evidence from human cancer and animal models that has aided our understanding of the role of autophagy in tumour progression. Finally, the potential for targeting autophagy therapeutically is discussed in light of the functions of autophagy at different stages of tumour progression and in normal tissues.
Among inbred female cotton rats (Sigmodon hispidus) 25-50% of the animals develop spontaneous gastric carcinomas; the corresponding figure for male cotton rats is approximately 1%. Animals with carcinomas have hypergastrinaemia and gastric hypo-anacidity and the tumours are derived from enterochromaffin-like (ECL) cells. The mechanism behind the hypo-anacidity is unknown. Carcinomas are found in all female cotton rats with hypergastrinaemia lasting more than 4 months and this represents an excellent animal model for studying gastric carcinogenesis. In this study, the somatostatin analogue octreotide was given to female cotton rats to prevent carcinoma development caused by hypergastrinaemia. Twelve female cotton rats were given monthly injections of long-acting octreotide (5 mg i.m.) for 6 months. A control group of 20 animals was not given injections. Of the 20 control animals, 13 developed hypergastrinaemia and histologically invasive carcinomas or dysplasia. Of the 12 animals in the octreotide group, five developed hypergastrinaemia. None of these five animals developed histological cancer (P<0.05), whereas three had dysplasia. However, octreotide did not affect plasma gastrin concentration or antral gastrin mRNA abundance significantly. Dysplasia of the oxyntic mucosa in hypergastrinaemic animals was accompanied by a marked increase in chromogranin A-immunoreactive cells and cells positive for Sevier-Munger staining. The malignant tissue also contained groups of cells with Sevier-Munger staining. In conclusion, octreotide prevented ECL cell carcinomas in hypergastrinaemic cotton rats without lowering the gastrin concentration.
Spontaneously hypergastrinemic cotton rats (Sigmodon hispidus) develop tumors that have the phenotype of an adenocarcinoma but most likely originate from the enterochromaffin-like (ECL) cells. Among inbred animals approximately 50% of the females, but <1% of males develop spontaneous gastric carcinomas. Gastrin is the principle carcinogen in this model, as >4 months of hypergastrinemia results in carcinoma, but a gastrin receptor antagonist prevents carcinomas. Carcinomas can also be induced by partial corpectomy. In the present study, the insurmountable H2-receptor antagonist loxtidine (200 mg/kg/day) was given to male cotton rats for 6 months. The loxtidine-dosed animals developed hypergastrinemia, whereas control animals remained normogastrinemic. At termination, 4 of 5 cotton rats had cancer located to the oxyntic mucosa, whereas 1 animal had dysplasia. The gastric mucosa of all of the control animals was normal. In the dysplastic mucosa of loxtidine-dosed animals there was a marked increase in chromogranin A-positive cells, where numerous groups of cells also stained positive with the Sevier-Munger technique. In areas of high proliferation and cancer there were also histidine decarboxylase, chromogranin A, and Sevier-Munger-positive cells, altogether indicating an ECL cell origin of the tumors. This represents an interesting animal model where ECL cell-derived gastric cancer can be induced by pharmacological acid inhibition in 6 months.
Caspase-8 and caspase-9 play crucial roles in the extrinsic and intrinsic apoptotic pathways, respectively. The nuclear translocation of apoptosis-inducing factor (AIF) is involved in caspase-independent apoptosis. Microtubule-associated protein 1 light chain 3 (LC3) plays a pivotal role in autophagy. In the present study, we analyzed the expression of cleaved caspase-8 (CC8), cleaved caspase-9 (CC9), AIF, and LC3 in 160 gastrointestinal adenocarcinomas. The nuclear expression of AIF was rare. The expression of CC8 in gastric and colorectal adenocarcinomas did not differ, whereas the percentage of CC9-positive tumors in gastric adenocarcinomas was significantly higher than in colorectal adenocarcinomas. In contrast, the percentage of LC3-positive tumors in gastric adenocarcinomas was significantly lower than in colorectal adenocarcinomas. CC8 and CC9 occasionally co-existed in the same tumor cells in gastric adenocarcinoma. However, LC3-positive tumor cells in colorectal adenocarcinomas were constantly negative for CC8. No correlation was identified between the expression of any markers and clinicopathological parameters. These results suggest that different cell death pathways are activated in a manner that depends upon the primary site and cell type. The extrinsic and intrinsic apoptotic pathways may be mutually regulated in gastric adenocarcinomas. Also, autophagy may function as a cellular guardian to avoid apoptosis in colorectal adenocarcinomas.
Hypergastrinemia occurs frequently in association with acid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined.
The effects of hypergastrinemia, and possible synergy with Helicobacter felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice.
INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor alpha. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (< or = 8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P < or = 0.05).
These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer.
Recently, autophagy has been demonstrated to modulate tumourigenesis and the response to cancer therapy by regulating numerous cellular functions including maintenance of cell viability under metabolic stress, mitochondrial homeostasis, regulation of reactive oxygen species accumulation, maintenance of genomic integrity, protein quality control, establishment of oncogene-induced senescence and regulation of tissue inflammation and tumour immunogenicity. Autophagy determines these different phenotypes of the tumour cell via diverse effector mechanisms, either involving buffering of metabolism or sequestration of specific proteins and organelles from the cytosol. We argue that the key to understanding the net effect of autophagy in controlling tumourigenesis will be to functionally dissect these different effector mechanisms. This will be enabled by the identification of how these are regulated by intracellular signalling pathways. Further investigation of these pathways will reveal how individual autophagy outcomes might be selectively targeted for therapeutic gain.
Autophagy, or cellular self-digestion, is activated in cancer cells in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance. Nonetheless, genetic evidence supports that autophagy functions as a tumor suppressor mechanism. Hence, the precise role of autophagy during cancer progression and treatment is both tissue and context dependent. Here, we discuss our current understanding of the biological functions of autophagy during cancer development, overview how autophagy is regulated by cancer-associated signaling pathways, and review how autophagy inhibition is being exploited to improve clinical outcomes.
Macroautophagy (autophagy) is a lysosomal degradation pathway for the breakdown of intracellular proteins and organelles. Although constitutive autophagy is a homeostatic mechanism for intracellular recycling and metabolic regulation, autophagy is also stress responsive, in which it is important for the removal of damaged proteins and organelles. Autophagy thereby confers stress tolerance, limits damage, and sustains viability under adverse conditions. Autophagy is a tumor-suppression mechanism, yet it enables tumor cell survival in stress. Reconciling how loss of a prosurvival function can promote tumorigenesis, emerging evidence suggests that preservation of cellular fitness by autophagy may be key to tumor suppression. As autophagy is such a fundamental process, establishing how the functional status of autophagy influences tumorigenesis and treatment response is important. This is especially critical as many current cancer therapeutics activate autophagy. Therefore, efforts to understand and modulate the autophagy pathway will provide new approaches to cancer therapy and prevention.
Autophagy or "self-eating" digests proteins and functionless cell organelles to reuse. This cell-own recycling system attracts much attention in tumour biology. One of the major functions of autophagy is maintaining cellular homeostasis. Thus, it is constitutive active in all living cells. Damaged or dispensable proteins and organelles are removed to regulate composition and size of the cytoplasm. Many therapeutic treatments have been shown to modulate autophagy signalling although it is still unclear if autophagy represents a survival or a suicide mechanism for tumour cells. Tumour growth in response to blocked autophagy as well as tumour growth in response to induced autophagy has been described. Several recent review articles address the differential effect of autophagy manipulation to apoptosis signalling. However, less has been reported about interactions of autophagy manipulation to the outcome of cancer therapy and tumour growth. Therefore, this review tries to fill this gap. We discuss data demonstrating that cellular decisions to autophagy manipulation depend on tumour type, stage, microenvironment, autophagy initiator or inhibitor and combined tumour treatment. Finally, we come to the conclusion that further analyses are necessary before manipulation of autophagic mechanisms can find its way into tumour therapy for improved treatment of patients.
Mounting evidence indicates that alterations of autophagy processes are directly involved in the development of many human diseases, including cancers. Autophagy-related gene (ATG) products are main players in the autophagy process. In humans there are 16 known ATG genes, of which four (ATG2B, ATG5, ATG9B and ATG12) have mononucleotide repeats with seven or more nucleotides. Frameshift mutations of genes with mononucleotide repeats are features of cancers with microsatellite instability (MSI). It is not known whether ATG genes with mononucleotide repeats are altered by frameshift mutations in gastric and colorectal carcinomas with MSI. For this, we analysed the mononecleotide repeats in ATG2B, ATG5, ATG9B and ATG12 in 32 gastric carcinomas with high MSI (MSI-H), 13 gastric carcinomas with low MSI (MSI-L), 43 colorectal carcinomas with MSI-H and 15 colorectal carcinomas with MSI-L by a single-strand conformation polymorphism (SSCP) analysis. We found ATG2B, ATG5, ATG9B and ATG12 mutations in 10, 2, 13 and 0 cancers, respectively. The mutations were detected in MSI-H cancers but not in MSI-L cancers. Gastric and colorectal cancers with MSI-H harboured one or more ATG mutations in 28.1% and 27.9%, respectively. Our data indicate that frameshift mutations in ATG genes with mononucleotide repeats are common in gastric and colorectal carcinomas with MSI-H, and suggest that these mutations may contribute to cancer development by deregulating the autophagy process.
Autophagy is a cellular self-catabolic process in which cytoplasmic constituents are sequestered in double membrane vesicles that fuse with lysosomes where they are degraded. As this catabolic activity generates energy, autophagy is often induced under nutrient limiting conditions providing a mechanism to maintain cell viability and may be exploited by cancer cells for survival under metabolic stress. However, progressive autophagy can be cytotoxic and autophagy can under certain settings substitute for apoptosis in induction of cell death. Moreover, loss of autophagy is correlated with tumorigenesis and several inducers of autophagy are tumor-suppressor genes. Thus, the relation of autophagy to cancer development is complex and depends on the genetic composition of the cell as well as on the extra-cellular stresses a cell is exposed to. In this review we describe the intricate nature of autophagy and its regulators, particularly those that have been linked to cancer. We discuss the multifaceted relation of autophagy to tumorigenesis and highlight studies supporting a role for autophagy in both tumor-suppression and tumor-progression. Finally, various autophagy-targeting therapeutic strategies for cancer treatment are presented.
Some studies have shown that the change of autophagic capacity may correlate with malignant transformation. Our study was designed to investigate the expression and significance of two autophagy-related proteins, microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 in the tumorigenesis and development of epithelial ovarian carcinoma. We observed that the positive expression of LC3 and Beclin 1 was significantly higher in the samples of benign and borderline ovarian tumors than those in malignant epithelial ovarian cancers. The expression of LC3 and Beclin 1 was associated with FIGO stage and histological grade. No significant relationship was observed between age and histological grade. However, we observed that the expression of LC3 was not related to Beclin 1. Therefore, the decrease of autophagic capacity may be related to tumorigenesis and development of epithelial ovarian cancer.
Addendum: Shen Y, Liang LZ, Hong MH, Xiong Y, Wei M, Zhu XF. Expression and clinical significance of microtubule-associated protein 1 light chain 3 (LC3) and Beclin1 in epithelial ovarian cancer. Ai Zheng 2008; 27:595-9.
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In our inbred strain of cotton rats (Sigmodon hispidus) 50% of the females develop spontaneous ECL cell-derived tumors in the acid-producing part of the stomach due to hypergastrinemia secondary to gastric hypoacidity. Although the mechanism behind the hypoacidity is unknown, the female cotton rat is an excellent model for studying ECL cell-related tumorigenesis. In this study we wanted to explore the malignancy potential of these tumors and the ability of a gastrin receptor antagonist (YF476) to prevent their development. First, nine hypergastrinemic female cotton rats (10 months of age) were diagnosed by laparotomy as having gastric tumors. They were killed 6 months later. Second, 18 female cotton rats (2 months of age) were dosed monthly for 6 months with YF476 (500 micro mol/kg body wt) by s.c. injection, while 21 age-matched animals received vehicle. Samples from each stomach were collected for histology, immunohistochemistry and northern blot analysis. The gastric tumors harbored cells with immunohistochemical features of ECL cells. The tumors were found at times to invade and penetrate the stomach wall and to metastasize to perigastric sites. ECL-derived tumor cells were discovered in peritoneal fluid. At death only 1 out of 18 animals given YF476 displayed carcinomas (invasive growth), compared with 7 out of 21 in the vehicle dosed control group (P = 0.048). The spontaneous gastric tumors in cotton rats derived from ECL cells. The tumors were able to penetrate the stomach wall and to metastasize by intracavital seeding. Gastrin receptor blockade lowered the incidence of such tumors. We propose that the tumors are ECL cell carcinomas and that gastrin is the driving force behind the transformation from normal to malignant ECL cells.
The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
Beclin 1, identified as a Bcl-2-interacting protein, is known to enhance autophagy. However, the effect of Beclin 1 on apoptotic signaling has remained unclear. Here, we show that overexpression of Beclin 1 in MKN28 human gastric cancer cells augmented cis-diamminedichloroplatinum (CDDP)-induced apoptosis. Conversely, "knockdown" of Beclin 1 by a small inhibitory RNA in MKN 1 cells attenuated this cytotoxicity. Furthermore, not only caspase-3/7 activities, but also caspase-9 activity was increased in Beclin 1 gene transfectants treated with CDDP, and caspase-9 inhibitor completely abolished augmentation of CDDP-induced apoptosis by Beclin 1 as did a caspase-3 inhibitor. Thus, Beclin 1 augments CDDP-induced apoptosis through enhancing caspase-9 activity and functions as a pro-apoptotic molecule.
The role of enterochromaffin-like (ECL) cells in gastric carcinogenesis is not fully understood. Spontaneous tumours developing in hypergastrinemic female cotton rats have an adenocarcinoma phenotype, but numerous cells in the dysplastic mucosa as well as in the carcinomas are positive for neuroendocrine markers. In the present study of female cotton rats with 2 and 8 months' hypergastrinemia, the oxyntic mucosa of the stomach was examined histologically and immunolabelled for histidine decarboxylase (HDC) and pancreastatin, and hyperplastic and neoplastic ECL cells were evaluated by electron microscopy. These animals developed hyperplasia of the oxyntic mucosa in general and of the ECL cells in particular after 2 months and dysplasia and carcinomas after 8 months. The immunoreactivity of the ECL cells in the oxyntic mucosa was increased at 2 months and declined at 8 months. These histological changes were associated with progressive loss of secretory vesicles and granules in ECL cells. We suggest that ECL cells in hypergastrinemic cotton rats dedifferentiate with time and that the gastric carcinomas may develop from ECL cells.
Cells rely on autophagy to recycle their components, and much evidence favors the idea that this "self-eating" suppresses tumor development. But other data suggest that autophagy fosters tumor development and actually protects cancer cells from treatments. ([Read more][1].)
[1]: http://www.sciencemag.org/cgi/content/full/312/5777/1160
Autophagy is a physiological and evolutionarily conserved phenomenon maintaining homeostatic functions like protein degradation and organelle turnover. It is rapidly upregulated under conditions leading to cellular stress, such as nutrient or growth factor deprivation, providing an alternative source of intracellular building blocks and substrates for energy generation to enable continuous cell survival. Yet accumulating data provide evidence that the autophagic machinery can be also recruited to kill cells under certain conditions generating a caspase-independent form of programed cell death (PCD), named autophagic cell death. Due to increasing interest in nonapoptotic PCD forms and the development of mammalian genetic tools to study autophagy, autophagic cell death has achieved major prominence, and is recognized now as a legitimate alternative death pathway to apoptosis. This chapter aims at summarizing the recent data in the field of autophagy signaling and autophagic cell death.
Autophagy plays important roles in both cell death and cell survival. Beclin-1, a key regulator of autophagy formation, has been considered as a haploinsufficient tumor suppressor. Loss of expression or point mutation could serve as a mechanism of loss of beclin-1 tumor suppressor function in cancers. However, our recent study revealed that point mutation of the beclin-1 gene is a rare event in common human cancers. In this study we investigated beclin-1 protein expression in 103 colorectal and 60 gastric carcinoma tissues by immunohistochemistry using a tissue microarray approach. In the cancers, expression of beclin-1 was detected in 95% of the colorectal carcinomas and 83% of the gastric carcinomas. In contrast, normal mucosal cells of both stomach and colon showed no or very weak expression of beclin-1. There was no significant association of beclin-1 expression with clinocopathologic characteristics, including invasion, metastasis and stage. The beclin-1 expression of colorectal and gastric cancers in the present study is quite in contrast to that of the breast cancers in the previous study, which showed a decreased beclin-1 expression in breast cancer cells compared to normal breast cells. Our data indicate that beclin-1 inactivation by loss of expression may not occur in colorectal and gastric cancers. Rather, increased expression of beclin-1 in the malignant colorectal and gastric epithelial cells compared to their normal mucosal epithelial cells suggests that neo-expression of beclin-1 may play a role in both colorectal and gastric tumorigenesis.
Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
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