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Expansion of neonatal acinar tissue by proliferation and hypertrophy. Immunohistochemical staining for amylase (a,c) and haematoxylin-eosin staining (b,d) on pancreas from ElaCreERT R26-YFP mice at 1-week (a,b) and 4-weeks (c,d) of age shows differential pancreas morphology during neonatal development. Analysis of acinar proliferation by immunohistochemical staining for amylase and Ki67 was performed at different time points (e-h). Acinar cell size (i) and cellularity of acini (j) at indicated time points. Shown are representative photomicrographs at original magnification of ×20. Results are expressed as mean ± SEM. All data were analysed by 1-way ANOVA, followed by Bonferroni's multiple comparison test (comparisons of interest: w1-w2, w2-w4, w1-w4; n1-w1, n4-w4, n1-n4). Results are considered statistically significant when P < 0.05. *: P < 0.05, **: P < 0.01, *** or °°°: P < 0.001. (°°°) indicates P-value compared to all previous time points. Detailed information about numbers of analysed mice, cells and acini can be found in Table 1.
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Pancreatic acinar cells secrete digestive enzymes necessary for nutrient digestion in the intestine. They are considered the initiating cell type of pancreatic cancer and are endowed with differentiation plasticity that has been harnessed to regenerate endocrine beta cells. However, there is still uncertainty about the mechanisms of acinar cell for...
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... acinar tissue expands by acinar cell proliferation and hypertrophy. The pancreas mor- phology undergoes significant alterations during neonatal development. Initially, the acinar tissue is compact and dense at 1 week of age (Fig. 2a,b). But by week 4, the morphology of the pancreas becomes indistinguishable from an adult mouse (Fig. 2c,d). As the pancreatic weight greatly augments from week 1 to week 4 ( Fig. 1b) and the majority of the pancreatic volume consists of acinar cells, there is thus a substantial increase in acinar mass in the neonatal period. Ki67 ...
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... acinar tissue expands by acinar cell proliferation and hypertrophy. The pancreas mor- phology undergoes significant alterations during neonatal development. Initially, the acinar tissue is compact and dense at 1 week of age (Fig. 2a,b). But by week 4, the morphology of the pancreas becomes indistinguishable from an adult mouse (Fig. 2c,d). As the pancreatic weight greatly augments from week 1 to week 4 ( Fig. 1b) and the majority of the pancreatic volume consists of acinar cells, there is thus a substantial increase in acinar mass in the neonatal period. Ki67 staining shows massive proliferation of pancreatic acinar cells in this period ( Fig. 2e-h). More than 40% of ...
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... from an adult mouse (Fig. 2c,d). As the pancreatic weight greatly augments from week 1 to week 4 ( Fig. 1b) and the majority of the pancreatic volume consists of acinar cells, there is thus a substantial increase in acinar mass in the neonatal period. Ki67 staining shows massive proliferation of pancreatic acinar cells in this period ( Fig. 2e-h). More than 40% of amylase + cells are positive for Ki67 at the age of 1 week. This is in sharp contrast with the proliferation level in adult acinar cells where less than 2% are Ki67 + 31 . The proliferation level gradually decreases in the next few weeks after birth (Fig. 2f-h). Further, there were no clear indications for a regional ...
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... massive proliferation of pancreatic acinar cells in this period ( Fig. 2e-h). More than 40% of amylase + cells are positive for Ki67 at the age of 1 week. This is in sharp contrast with the proliferation level in adult acinar cells where less than 2% are Ki67 + 31 . The proliferation level gradually decreases in the next few weeks after birth (Fig. 2f-h). Further, there were no clear indications for a regional difference in acinar proliferation in pancreatic tissue (border/centre of tissue, peri-insular/tele-insular) at all ages ...
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... acinar cell proliferation, also acinar hypertrophy contributes to the increase in acinar cell mass as the acinar cell size increases by 48-80% between week 1 and week 4 in TAM and non-TAM-treated animals, respec- tively ( Fig. 2i). TAM administration had no significant effect on proliferative activity of acinar cells but slightly reduced the increase in acinar cell size. Further, quantification of cellularity of acini revealed that the mean num- ber of acinar nuclei per acinus is 9.3 ± 0.2 (n = 4) in 1-week old TAM-treated mice and that this number does not ...
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... significant effect on proliferative activity of acinar cells but slightly reduced the increase in acinar cell size. Further, quantification of cellularity of acini revealed that the mean num- ber of acinar nuclei per acinus is 9.3 ± 0.2 (n = 4) in 1-week old TAM-treated mice and that this number does not significantly differ at all ages analysed (Fig. ...
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... other results are expressed as mean ± SEM. All data were analysed by unpaired two-tailed t-test (Fig. 4a,b,e) or 1-way ANOVA (Figs 1a,b,c, 2h,i,j and 3c), followed by Bonferroni's multiple comparison test (comparisons of interest: w1-w2, w2-w4, w1-w4; n1-w1, n4-w4, n1-n4. For Fig. 1c: n1-w1, n4-w4); after normality testing. ...
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Citations
... Inspection of the DAPI staining further indicated that exocrine pancreas at P15 contained a higher number of nuclei per ROI (Figs. 6e, k and 7e, k, q) compared to the other investigated ages and that at P84 the cytoplasm of the acinar cells was enlarged (Fig. 6f, l and 7f, l, r). These observations hint to cell proliferation and/or cell hypertrophy events occurring in the postnatal period as previously observed (Houbracken and Bouwens 2017). ...
... peroxisome number per nucleus, is an indication for the number of peroxisomes per cell. This information is particularly important as mouse acinar cells of the pancreas are known to proliferate drastically in the first 4 weeks of life (Houbracken and Bouwens 2017). ...
... During postnatal development, the acinar population is first expanded through numerous mitotic divisions from preexisting acini during the suckling period (first and second week) (Houbracken and Bouwens 2017). Thereafter, the cells of the pancreatic acini grow through hypertrophy and display vastly enlarged cytoplasm at week 4. ...
Peroxisomal dysfunction unhinges cellular metabolism by causing the accumulation of toxic metabolic intermediates (e.g. reactive oxygen species, very -chain fatty acids, phytanic acid or eicosanoids) and the depletion of important lipid products (e.g. plasmalogens, polyunsaturated fatty acids), leading to various proinflammatory and devastating pathophysiological conditions like metabolic syndrome and age-related diseases including diabetes. Because the peroxisomal antioxidative marker enzyme catalase is low abundant in Langerhans islet cells, peroxisomes were considered scarcely present in the endocrine pancreas. Recently, studies demonstrated that the peroxisomal metabolism is relevant for pancreatic cell functionality. During the postnatal period, significant changes occur in the cell structure and the metabolism to trigger the final maturation of the pancreas, including cell proliferation, regulation of energy metabolism, and activation of signalling pathways. Our aim in this study was to (i) morphometrically analyse the density of peroxisomes in mouse endocrine versus exocrine pancreas and (ii) investigate how the distribution and the abundance of peroxisomal proteins involved in biogenesis, antioxidative defence and fatty acid metabolism change during pancreatic maturation in the postnatal period. Our results prove that endocrine and exocrine pancreatic cells contain high amounts of peroxisomes with heterogeneous protein content indicating that distinct endocrine and exocrine cell types require a specific set of peroxisomal proteins depending on their individual physiological functions. We further show that significant postnatal changes occur in the peroxisomal compartment of different pancreatic cells that are most probably relevant for the metabolic maturation and differentiation of the pancreas during the development from birth to adulthood.
... Another study found that Sox9-positive pancreatic ductal epithelia are progenitors for acinar cells under physiological condition 12 . However, several studies using lineage tracing strategy found that the exocrine acinar cells regenerated mainly by self-replication [13][14][15][16][17] . In addition, two ductal cell lineage tracing studies suggested no contribution of ductal cells to acinar cells in adults 18,19 . ...
... Immunostaining for tdT, zsGreen, CK19 or Amylase on pancreatic tissue sections revealed that all acinar cells expressed tdT but not ZsGreen, while pancreatic ductal cells expressed ZsGreen but not tdT ( Fig. 2c-e). These fate-mapping results suggest that during homeostasis in the adult mouse pancreas, new ductal cells and acinar cells mainly arise from selfduplication rather than lineage transdifferentiation (Fig. 2f), in line with previous results using other lineage tracing approaches [13][14][15][16][17][18][19] . ...
Unraveling cell fate plasticity during tissue homeostasis and repair can reveal actionable insights for stem cell biology and regenerative medicine. In the pancreas, it remains controversial whether lineage transdifferentiation among the exocrine cells occur under pathophysiological conditions. Here, to address this question, we used a dual recombinase-mediated genetic system that enables simultaneous tracing of pancreatic acinar and ductal cells using two distinct genetic reporters, avoiding the “ectopic” labeling by Cre-loxP recombination system. We found that acinar-to-ductal transdifferentiation occurs after pancreatic duct ligation or during caerulein-induced pancreatitis, but not during homeostasis or after partial pancreatectomy. On the other hand, pancreatic ductal cells contribute to new acinar cells after significant acinar cell loss. By genetic tracing of cell proliferation, we also quantify the cell proliferation dynamics and deduce the turnover rate of pancreatic exocrine lineages during homeostasis. Together, these results suggest that the lineage transdifferentiation happens between acinar cells and ductal cells in the pancreatic exocrine glands under specific conditions.
... In contrast to such adaptive proliferation, basal bcell proliferation rates under normal conditions are very low during adulthood, 5,9 compared with those in other intraabdominal organs, such as the liver, gastrointestinal tract, and the exocrine pancreas, which show ongoing active cell proliferation. [10][11][12][13] The extent of involvement of basal and low-level proliferation in maintaining sufficient b-cells during adulthood †These authors contributed equally to this work. ...
Aims/introduction:
Whether basal β-cell proliferation during adulthood is involved in maintaining sufficient β-cell mass, and if so, the molecular mechanism(s) underlying basal β-cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in "adaptive" β-cell proliferation, which facilitates rapid increases in β-cell mass in response to increased insulin demands. Therefore, we herein focused on the roles of β-cell FoxM1 in "basal" β-cell proliferation under normal conditions and maintenance of sufficient β-cell mass as well as glucose homeostasis during adulthood.
Materials and methods:
FoxM1 deficiency was induced specifically in β-cells of 8-week-old mice, followed by analyzing its short (2 weeks)- and long (10 months)-term effects on β-cell proliferation, β-cell mass and glucose tolerance.
Results:
FoxM1 deficiency suppressed β-cell proliferation at both ages, indicating critical roles of FoxM1 in basal β-cell proliferation throughout adulthood. While short-term FoxM1 deficiency affected neither β-cell mass nor glucose tolerance, long-term FoxM1 deficiency suppressed β-cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, insulin secretory function was not impaired in islets isolated from mice subjected to long-term β-cell FoxM1 deficiency. Therefore, β-cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long-term β-cell FoxM1 deficiency.
Conclusions:
Basal low-level proliferation of β-cells during adulthood is important for maintaining sufficient β-cell mass and good glucose tolerance and β-cell FoxM1 underlies this mechanism. Preserving β-cell FoxM1 activity may prevent impairment of glucose tolerance with advancing age.
... The extensive proliferation and expansion of developing pancreatic tissue allows for clonal tracing during this period. This is in contrast to the adult pancreatic tissue, which is rather dormant, as reflected by its proliferation rates: less than 2% of the cells proliferate in the adult pancreas compared to~40% directly postnatally [49]. As a consequence, our understanding of the clonal dynamics and the exact process of renewal of the exocrine cells during homeostasis in the adult pancreas is limited, as assays that would assess that this takes a lot of time [2,29]. ...
... In particular, it remains unclear whether a specific subpopulation of the exocrine pancreas has the ability to generate new cells, and thereby functions as stem-like cells in the adult pancreas, or if all mature cells have these properties. Despite the low turnover rate in the adult pancreas, few lineage tracing studies have been performed from mature acinar cells postnatally and during homeostasis [49][50][51][52][53]. In these studies, it was demonstrated that cell lineages become restricted and that self-duplication is the main mechanism of tissue development postnatally ( Figure 1). ...
Cell generation and renewal are essential processes to develop, maintain, and regenerate tissues. New cells can be generated from immature cell types, such as stem-like cells, or originate from more differentiated pre-existing cells that self-renew or transdifferentiate. The adult pancreas is a dormant organ with limited regeneration capacity, which complicates studying these processes. As a result, there is still discussion about the existence of stem cells in the adult pancreas. Interestingly, in contrast to the classical stem cell concept, stem cell properties seem to be plastic, and, in circumstances of injury, differentiated cells can revert back to a more immature cellular state. Importantly, deregulation of the balance between cellular proliferation and differentiation can lead to disease initiation, in particular to cancer formation. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of only ~9%. Unfortunately, metastasis formation often occurs prior to diagnosis, and most tumors are resistant to current treatment strategies. It has been proposed that a specific subpopulation of cells, i.e., cancer stem cells (CSCs), are responsible for tumor expansion, metastasis formation, and therapy resistance. Understanding the underlying mechanisms of pancreatic stem cells during homeostasis and injury might lead to new insights to understand the role of CSCs in PDAC. Therefore, in this review, we present an overview of the current literature regarding the stem cell dynamics in the pancreas during health and disease. Furthermore, we highlight the influence of the tumor microenvironment on the growth behavior of PDAC.
... The number of Ki67 + cells per tissue area significantly decreased over time in both Kras WT tissues and KrasG12D (p < 0.004; Figure S2C). This is consistent with reports that cell proliferation decreases in aging pancreas tissues over time, 27,28 and it implies that changes in cell proliferation rates are unlikely to contribute to the clearance of KrasG12D cells from KC tissues. ...
As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbors for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that before being cleared, KrasG12D cells lose cell volume, pack into round clusters, and E-cadherin-based cell-cell adhesions decrease at boundaries with normal neighbors. We identify EphA2 receptor as an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells do not alter cell volume or shape, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. The retention of KRasG12D cells leads to the early appearance of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumor suppressor in pancreatic cancer.
... The lobes were formed from densely grouped exocrine units called acini constructed from pyramidal epithelial cells, characterized by apical zymogene granules with basally located nuclei separated from each other by very fine connective tissue septae. Similar observation was previously recorded in other species such as mouse (Houbracken and Bouwens, 2017), cat (Al-Saffar and Al-Zuhairy, 2017) and rat (Fattah, 2008). ...
The pancreas is an organ of special interest from a medical viewpoint as it is the target of two major diseases;
diabetes mellitus and pancreatic cancer. The present study was conducted to investigate the histoarchitecture and
histochemical aspects of the exocrine portion of the pancreas in the adult male and female guinea pigs. Eight animals
of each sex were used to perform the project. Specimens were either fixed using 10% neutral buffered formalin or
Bouin's solution. Tissues sections were stained using different stains such as hematoxylin and eosin (H&E),
Masson's Trichrome (MTC), Periodic acid Schiff (PAS), Alcian blue (AB) (pH 2.5) and a combination of the last two
stains. Exocrine portion of the pancreas formed up nearly the whole of the pancreas. It was constructed of different
sized lobules of well-formed parenchyma made by densely packed acinar units. The parenchyma provided with well
duct system in which most of interlobular ducts were lined by simple columnar epithelium with goblet cells
associated with subepithelial mucous glands. The main (minor pancreatic) duct was surrounded by supporting
connective tissue which possessed smooth muscle fibers. Unique histological features of the pancreas in Guinea pigs
were recorded such as only the wall of minor pancreatic duct having smooth muscle fibers that was supportive to
the duct till its entrance the duodenal wall and most branches of the duct system were lined by columnar epithelium
with goblet cells reacted positively toward both PAS and AB staining procedures. Autonomic ganglia were detected
only in the body lobe adjacent to the large and larger interlobular ducts and vessels in the pancreas.
... The lobes were formed from densely grouped exocrine units called acini constructed from pyramidal epithelial cells, characterized by apical zymogene granules with basally located nuclei separated from each other by very fine connective tissue septae. Similar observation was previously recorded in other species such as mouse (Houbracken and Bouwens, 2017), cat (Al-Saffar and Al-Zuhairy, 2017) and rat (Fattah, 2008). ...
Background and objective: Pancreas is an organ of special interest from a medical viewpoint as it is the target of two major diseases that are diabetes mellitus and pancreatic cancer. The present study was conducted to investigate the histoarchitecture and histochemical aspects of the exocrine portion of the pancreas in the adult males and females guinea pigs. Materials and methods: Eight animals of each sex were collected to perform the project. Specimens were fixed by 10% neutral buffered formalin and others by Bouin's solution. Post routine histological procedure, different stains were used to stain the sections such as hematoxylin and eosin (H&E), Masson's Trichrome (MTC), Periodic acid Schiff (PAS), Alcian blue (AB)(pH 2.5) and the combination of the last two stains. Results: Exocrine portion of the pancreas formed up nearly the whole of the pancreas. It was constructed of different sized lobules of well formed parenchyma made by densely packed acinar units. The parenchyma provided with well duct system in which most of interlobular ducts were lined by simple columnar epithelium with goblet cells associated with subepithelial mucous glands. The main (minor pancreatic) duct was surrounded by supporting connective tissue which possessed smooth muscle fibers. Conclusions: Unique histological features were recorded such as only the wall of minor pancreatic duct having smooth muscle fibers that was supportive to the duct till its entrance the duodenal wall and most branches of the duct system were lined by columnar epithelium with goblet cells reacted positively toward both PAS and (AB) (pH 2.5) staining procedures. Autonomic ganglia were detected only in the body lobe adjacent to the large and larger interlobular ducts and vessels in the pancreas.
Key words: pancreas, guinea pig, acini, pancreatic duct, histochemistry
... Pancreatic acinar cells can regenerate damaged tissue by initiating a proliferative process after AP (Bombardo et al., 2018). Studies suggest that new acinar cells are regenerated almost exclusively from the division and self-duplication of pre-existing acinar cells (Desai et al., 2007;Houbracken and Bouwens, 2017). The proliferation was used to assess regeneration of acute pancreatitis (Keefe et al., 2012). ...
Nuclear receptor subfamily 5 group A member 2 (Nr5a2) is widely involved in the physiological and pathological processes of the pancreas. However, the cytological and molecular evidence regarding how Nr5a2 implicated in acute pancreatitis (AP) remains insufficient. Here, we explored this problem by using cellular AP model in both normal and Nr5a2 silenced AR42J pancreatic acinar cells. An in vitro cellular model of AP was established by stimulating AR42J cells with caerulein (CAE) for 24 h. Reduced Nr5a2 expression was observed in the CAE-treated cells. Nr5a2 silencing led to AP-like inflammation, with increased interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α mRNA levels. In the cellular AP model, Nr5a2 silencing further increased IL-1β, IL-6, and TNF-α mRNA levels, as well as amylase activity. In addition, we found that Nr5a2 silencing did not affect IL-10 level under physiological conditions but inhibited the anti-inflammatory response of IL-10 in AP model. Moreover, in CAE-induced pancreatic inflammation, Nr5a2 silencing increased the apoptosis and necrosis of acinar cells and inhibited the proliferation of acinar cells, which has not been shown previously. Further experiments showed, for the first time, that Nr5a2 silencing downregulated the expression of β-catenin and its downstream target gene T-cell factor (TCF)-4 in the cellular AP model but increased the expression of nuclear factor (NF)-κB. In conclusion, in CAE-induced pancreatic inflammation, lower Nr5a2 level leads to downregulation of β-catenin and its downstream target gene TCF-4 and upregulation of NF-κB, which exacerbates the inflammatory response and cell damage and inhibits the proliferation and regeneration of acinar cells.
... Interestingly, a recent report suggests that acinar cells in neonatal pancreas regenerate by duplication rather than from ductal-tip cells. 140 Studies have shown a conserved group of Ptf1a + /Ela3l − progenitor cells in zebrafish capable of regenerating exocrine cells after loss of acinar tissue. 141 This report also suggests the possible role of Wnt signaling in maintaining acinar progenitor expansion. ...
... Here, we investigate its role in differentiated ducts after birth. In the post-natal pancreas, acinar cells do not derive from ducts 12,14,15 , allowing analysis of the role of Hnf1b in duct function and the consequences on acinar cell homeostasis. ...
... In order to investigate the role of Hnf1b in differentiated ducts after birth, we analyzed the expression of genes involved in the maintenance of the primary cilium and in ductal cell integrity and functionality ( Figure 1E). In Hnf1b∆ duct mutants, we found by RT-qPCR a significant decrease in expression of cystic disease genes, known as direct targets of Hnf1b in renal cells or in pancreatic progenitors [13][14][15][16][17] . We observed a strong decrease in Pkhd1, Cys1, Spp1 and Prox1 expression, involved in ciliary maintenance and/or tubular architecture [18][19][20][21] . ...
Background and aims. The exocrine pancreas consists of acinar cells that produce digestive enzymes transported to the intestine through a branched ductal epithelium. Chronic pancreatitis is characterized by progressive inflammation, fibrosis and loss of acinar tissue. These changes of the exocrine tissue are risk factors for pancreatic cancer. The cause of chronic pancreatitis cannot be identified in one-quarter of patients. Here, we investigated how duct dysfunction could contribute to pancreatitis development.
Methods. The transcription factor Hnf1b, first expressed in pancreatic progenitors, is strictly restricted to ductal cells from late embryogenesis. We have previously shown that Hnf1b is crucial for pancreas morphogenesis but its postnatal role still remains unelucidated. To investigate the role of pancreatic ducts in exocrine homeostasis, we inactivated Hnf1b gene in vivo in mouse ductal cells.
Results. We uncovered that postnatal Hnf1b inactivation in pancreatic ducts leads to chronic pancreatitis in adults. Hnf1bΔduct mutants display dilatation of ducts, loss of acinar cells, acinar-to-ductal metaplasia (ADM) and lipomatosis. We deciphered the early events involved, with downregulation of cystic disease-associated genes, loss of primary cilia, upregulation of signaling pathways, especially Yap pathway involved in ADM. Remarkably, Hnf1bΔduct mutants developed pancreatic intraepithelial neoplasia and promote PanIN progression in concert with KRAS. We further showed that adult Hnf1b inactivation in pancreatic ducts is associated with impaired regeneration after injury, with persistent metaplasia and initiation of neoplasia.
Conclusion. Loss of Hnf1b in ductal cells leads to chronic pancreatitis and neoplasia. This reveals that Hnf1b deficiency may contribute to diseases of the exocrine pancreas and could gain further insight into the etiology of pancreatitis and tumorigenesis.
