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Carbonate Ions and Gastric Cancer

Ehrnström, Roy LU (2007) In Lund University, Faculty of Medicine Doctoral Dissertation 2007:18.
Abstract (Swedish)
Popular Abstract in Swedish

Nästan en miljon nya fall av magsäckscancer diagnostiseras årligen världen över. Även om frekvensen har fallit dramatiskt de senaste åren så är magsäckscancern fortfarande den näst vanligaste orsaken till död i cancer sett ur ett världsperspektiv. Den geografiska variationen av denna cancertyp är anmärkningsvärd med den högsta förekomsten i asiatiska länder såsom Japan, Korea och Kina. Denna världsomspännande variation är sannolikt förknippad med riskfaktorer som går att förändra och de två riskfaktorer som dominerat debatten de senaste tio åren är: magsårsbakterien Helicobacter pylori och kostfaktorer. Frekvensen av spontan magsäckscancer hos råtta är en raritet och detta har lett till att man... (More)
Popular Abstract in Swedish

Nästan en miljon nya fall av magsäckscancer diagnostiseras årligen världen över. Även om frekvensen har fallit dramatiskt de senaste åren så är magsäckscancern fortfarande den näst vanligaste orsaken till död i cancer sett ur ett världsperspektiv. Den geografiska variationen av denna cancertyp är anmärkningsvärd med den högsta förekomsten i asiatiska länder såsom Japan, Korea och Kina. Denna världsomspännande variation är sannolikt förknippad med riskfaktorer som går att förändra och de två riskfaktorer som dominerat debatten de senaste tio åren är: magsårsbakterien Helicobacter pylori och kostfaktorer. Frekvensen av spontan magsäckscancer hos råtta är en raritet och detta har lett till att man med olika experimentella metoder försökt orsaka macksäckscancer. I vår första studie opererade vi bort nedersta delen av magsäcken för att skapa en reflux av de vätskor som finns i tolvfingertarmen, bukspottskörteln samt galla in i magsäcken och på så sätt utveckla spontan tumörbildning. I denna djurförsöksmodell studerades olika födoämnes-faktorers effekt på uppkomsten av magsäckscancer bland 256 manliga Wistar råttor. I den första omgången av studien fann vi överraskande att föda som tillförts kalciumkarbonat mer än trefalt ökade tumörförekomsten jämfört med kontroll gruppen (61% mot 17%). Genom att byta kalciumjoner mot natriumjoner kunde vi i en andra omgång av försöket visa att det var karbonatjonen som var ansvarig för den betydande ökningen av antalet cancrar (54% mot 12%). I både kliniska och experimentella studier är reflux av vätskor från tolvfingertarmen sammankopplad med utvecklingen av magsäckscancer. Dessutom är det visat att det är vätskan från bukspottskörteln och tolvfingertarmen snarare än gallan som är ansvarig för tumörutvecklingen och att dessa vätskor är särdeles rik på karbonatjoner. I den sista studien undersökte vi uttrycket av olika cancer relaterade proteiner såsom COX-2 och ODC samt tillväxtaktiviteten med hjälp av Ki67 i normal magsäcksslemhinna från opererade råttor för att kunna bedöma betydelsen av karbonatjoner för cancerutvecklingen. Resultaten visar att om man opererar bort nedersta delen av magsäcken ökar COX-2 uttrycket och tillväxtaktiviteten mätt med Ki67 stegras. Tillägg av karbonatjoner i födan ökar inte COX-2 nivåerna ytterliggare. Emellertid, bland opererande försöksdjur som erhållit kost med tillägg av karbonatjoner fann vi ett kraftigt förhöjt uttryck av ODC parallellt med en kraftigt stegrad tillväxtaktivitet. Det förefaller som om en enträgen kronisk inflammation med ökade COX-2 nivåer, förorsakad av till exempelvis reflux eller H pylori infektion, ökar risken att utveckla magsäckscancer. Föda med tillsats av karbonatjoner ökar påtagligt nivåerna av ODC i en COX-2-beroende miljö som i sin tur resulterar i en ytterliggare höljning av tillväxtaktiviteten och en ännu högre risk för utveckling av magsäckscancer. (Less)
Abstract
Nearly one million new cases of gastric cancer are diagnosed annually throughout the world. Even though the incidence has fallen dramatically in recent decades, this disease is still the second leading cause of cancer death in a global perspective. The geographic distribution of gastric cancer varies markedly, with the highest rates in Asian countries such as Japan, Korea, and China. This variation is presumably associated with modifiable risk factors, primarily H. pylori infection and diet, which have dominated the debate on this topic for more than a decade. The incidence of spontaneous gastric cancer is extremely low in rats, which has led to testing of different experimental models in attempts to generate gastric tumors in these... (More)
Nearly one million new cases of gastric cancer are diagnosed annually throughout the world. Even though the incidence has fallen dramatically in recent decades, this disease is still the second leading cause of cancer death in a global perspective. The geographic distribution of gastric cancer varies markedly, with the highest rates in Asian countries such as Japan, Korea, and China. This variation is presumably associated with modifiable risk factors, primarily H. pylori infection and diet, which have dominated the debate on this topic for more than a decade. The incidence of spontaneous gastric cancer is extremely low in rats, which has led to testing of different experimental models in attempts to generate gastric tumors in these animals. In the first study underlying this thesis, rats were subjected to gastric resection to generate duodenogastric reflux (DGR) and subsequent development of gastric adenocarcinomas. The effects of various food supplements on the incidence of cancer were studied using a total of 256 male Wistar rats. Surprisingly, in the first set of experiments in the second study, ingestion of food supplemented with calcium carbonate more than tripled the incidence of carcinomas (61%) compared to controls (17%). In a second set of experiments, calcium ions were switched to sodium ions, which revealed that carbonate ions caused the remarkable increase in cancer in the rats given an altered diet (54%, compared to 12% for controls). Both experimental and clinical studies have shown that DGR is associated with the development of gastric cancer. It has also been found that pancreaticoduodenal juice is responsible for the neoplastic formation, and that such fluid is especially rich in carbonate ions. The final study examined non-transformed mucosa in a rat model of gastric cancer to determine expression of COX-2 and ODC as markers of tumor promotion and to measure production of Ki67 as an indication of cell proliferation. This was done to assess the effect of carbonate ions on gastric tumorigenesis. The results indicated that the gastric resection per se increased COX-2 expression and significantly augmented cell proliferation. Dietary supplementation of carbonate ions did not further enhance the levels of COX-2. However, in the resected animals, carbonate-supplemented food led to elevated expression of ODC and a further increase in cell proliferation in the non-transformed mucosa. In conclusion, an environment entailing persistent chronic inflammation and increased levels of COX-2, induced by either duodenogastric reflux or a factor such as H. pylori infection, increases the risk of malignant transformation. Moreover, extra carbonate intake raises the levels of ODC in the gastric mucosa in a COX-2-dependent manner, which magnifies the proliferative drive and results in an even higher risk of gastric carcinoma. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Lundell, Lars, Enheten för Kirurgi, Karolinska Universitetssjukhetet, Stockholm
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicine (human and vertebrates), ODC, COX-2, inflammation, Wistar rats, duodenogastric reflux, Medicin (människa och djur), proliferation, gastrojejunostomy, carbonate ions, Experimental gastric cancer
in
Lund University, Faculty of Medicine Doctoral Dissertation
volume
2007:18
pages
110 pages
publisher
Lund University, Faculty of Medicine
defense location
Patologiska Institutionens föreläsnings-sal, Ingång 78, Universitetssjukhuset UMAS i Malmö
defense date
2007-02-09 09:00
ISSN
1652-8220
ISBN
91-85559-86-5
language
English
LU publication?
yes
id
d61b3b84-1ed9-4eae-b477-706908906e2e (old id 547957)
date added to LUP
2007-09-11 11:43:18
date last changed
2016-09-19 08:44:54
@phdthesis{d61b3b84-1ed9-4eae-b477-706908906e2e,
  abstract     = {Nearly one million new cases of gastric cancer are diagnosed annually throughout the world. Even though the incidence has fallen dramatically in recent decades, this disease is still the second leading cause of cancer death in a global perspective. The geographic distribution of gastric cancer varies markedly, with the highest rates in Asian countries such as Japan, Korea, and China. This variation is presumably associated with modifiable risk factors, primarily H. pylori infection and diet, which have dominated the debate on this topic for more than a decade. The incidence of spontaneous gastric cancer is extremely low in rats, which has led to testing of different experimental models in attempts to generate gastric tumors in these animals. In the first study underlying this thesis, rats were subjected to gastric resection to generate duodenogastric reflux (DGR) and subsequent development of gastric adenocarcinomas. The effects of various food supplements on the incidence of cancer were studied using a total of 256 male Wistar rats. Surprisingly, in the first set of experiments in the second study, ingestion of food supplemented with calcium carbonate more than tripled the incidence of carcinomas (61%) compared to controls (17%). In a second set of experiments, calcium ions were switched to sodium ions, which revealed that carbonate ions caused the remarkable increase in cancer in the rats given an altered diet (54%, compared to 12% for controls). Both experimental and clinical studies have shown that DGR is associated with the development of gastric cancer. It has also been found that pancreaticoduodenal juice is responsible for the neoplastic formation, and that such fluid is especially rich in carbonate ions. The final study examined non-transformed mucosa in a rat model of gastric cancer to determine expression of COX-2 and ODC as markers of tumor promotion and to measure production of Ki67 as an indication of cell proliferation. This was done to assess the effect of carbonate ions on gastric tumorigenesis. The results indicated that the gastric resection per se increased COX-2 expression and significantly augmented cell proliferation. Dietary supplementation of carbonate ions did not further enhance the levels of COX-2. However, in the resected animals, carbonate-supplemented food led to elevated expression of ODC and a further increase in cell proliferation in the non-transformed mucosa. In conclusion, an environment entailing persistent chronic inflammation and increased levels of COX-2, induced by either duodenogastric reflux or a factor such as H. pylori infection, increases the risk of malignant transformation. Moreover, extra carbonate intake raises the levels of ODC in the gastric mucosa in a COX-2-dependent manner, which magnifies the proliferative drive and results in an even higher risk of gastric carcinoma.},
  author       = {Ehrnström, Roy},
  isbn         = {91-85559-86-5},
  issn         = {1652-8220},
  keyword      = {Medicine (human and vertebrates),ODC,COX-2,inflammation,Wistar rats,duodenogastric reflux,Medicin (människa och djur),proliferation,gastrojejunostomy,carbonate ions,Experimental gastric cancer},
  language     = {eng},
  pages        = {110},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation},
  title        = {Carbonate Ions and Gastric Cancer},
  volume       = {2007:18},
  year         = {2007},
}