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Alpha 1-antitrypsin: A Role in Cancer Progression

Zelvyté, Inga LU (2004)
Abstract (Swedish)
Popular Abstract in Swedish

Alpha1-antitrypsin (AAT), som är ett cirkulerande glykoprotein, är den vanligast förekommande serinproteinashämmaren i plasman hos människa. Den ingår i gruppen av akutfasproteiner, och dess halt i plasma kan snabbt öka till koncentrationer överstigande 50 mM vid inflammation, infektion eller malign sjukdom. Då AAT fungerar som en effektiv hämmare av neutrofilelastas och proteinas 3, antar man att dess fysiologiska funktion är att skydda den egna vävnaden mot proteolytisk påverkan. Emellertid återfinns AAT inte enbart i en naiv, skyddande form, utan även i modifierade icke-skyddande former, såsom polymeriserad, spjälkad och/eller degraderad. Nya studier har visat att icke-skyddande former av AAT... (More)
Popular Abstract in Swedish

Alpha1-antitrypsin (AAT), som är ett cirkulerande glykoprotein, är den vanligast förekommande serinproteinashämmaren i plasman hos människa. Den ingår i gruppen av akutfasproteiner, och dess halt i plasma kan snabbt öka till koncentrationer överstigande 50 mM vid inflammation, infektion eller malign sjukdom. Då AAT fungerar som en effektiv hämmare av neutrofilelastas och proteinas 3, antar man att dess fysiologiska funktion är att skydda den egna vävnaden mot proteolytisk påverkan. Emellertid återfinns AAT inte enbart i en naiv, skyddande form, utan även i modifierade icke-skyddande former, såsom polymeriserad, spjälkad och/eller degraderad. Nya studier har visat att icke-skyddande former av AAT kan ha biologiska effekter, oberoende av dess hämmande effekten på serinproteinaserna. Syftet med de studier som denna avhandling är baserad på är att testa i cellodlingsförsök hypotesen att AAT både i sin naiva och i sina modifierade former har effekter på tumörceller. De cancerpatienter som har en hög halt av proteinashämmare har ofta en mer spridd sjukdom med sämre prognos. Vi fann i våra studier att plasmanivåerna av AAT, alpha1-antichymotrypsin och SLPI (secretory leukocyte protease inhibitor) är förhöjd hos patienter med nydiagnostiserad lungcancer. Detta sågs i större utsträckning vid metastaserande sjukdom. Våra resultat indikerar att proteinashämmare kan vara en bidragande faktor till tumörutveckling. Därför gick vi vidare med studier av den naiva och de modifierade formerna (polymeriserad och/eller C-terminala fragmentet, C-36) av AAT på humana neutrofiler och lungcancerceller där vi undersökte dem i separata men också i integrerade cellodlingsförsök. Vi fann att C-36 peptiden av AAT på ett koncentrationensberoende sätt inducerar neutrofilers kemotaxis, adhesion, degranulering och bildande av superoxider. Däremot fann vi att den naiva och den polymeriserade formen av AAT vid samma eller i högre koncentrationer saknade dessa effekter. I integrerade cellodlingsexperiment fann vi att den interaktion mellan lungcancerceller och som resulterar i neutrofilers degranulering påverkas av exogent tillfört AAT och C-36 peptid. Motsvarande experiment utförda med lung-, bröst- och pankreascancerceller visade att AAT, beroende på sin molekylära form, kan bidraga till eller motverka cancercellers proliferation, invasivitet och förmåga att frisätta vissa biomarkörer såsom tillväxtfaktorer, cytokiner och metalloproteinaser. Sammantaget stödjer våra fynd hypotesen att AATs betydelse för cancertillväxten inte enbart är begränsad till dess förmåga att hämma proteinaser utan har även andra direkta effekter på inflammatoriska celler och tumörceller. (Less)
Abstract
Alpha1-antitrypsin (AAT), a circulating single-chain glycoprotein is the most abundant serine proteinase inhibitor in human plasma. AAT is an acute phase protein, its levels increase rapidly to concentrations exceeding 50mM in response to inflammation, infection and malignant diseases. Since AAT is a powerful inhibitor of neutrophil elastase and proteinase 3, it is generally assumed that its physiological function is to protect host tissue from the proteolytic actions of these proteinases. However, in vivo AAT is found not only in the native, inhibitory form, but also modified non-inhibitory forms including polymerized, cleaved and/or degraded. Recent findings suggest that non-inhibitory forms of AAT may also express biological activity,... (More)
Alpha1-antitrypsin (AAT), a circulating single-chain glycoprotein is the most abundant serine proteinase inhibitor in human plasma. AAT is an acute phase protein, its levels increase rapidly to concentrations exceeding 50mM in response to inflammation, infection and malignant diseases. Since AAT is a powerful inhibitor of neutrophil elastase and proteinase 3, it is generally assumed that its physiological function is to protect host tissue from the proteolytic actions of these proteinases. However, in vivo AAT is found not only in the native, inhibitory form, but also modified non-inhibitory forms including polymerized, cleaved and/or degraded. Recent findings suggest that non-inhibitory forms of AAT may also express biological activity, un-related to serine proteinase inhibition. The overall aim of the studies upon which this thesis is based was to test a hypothesis that AAT in native and modified molecular forms may exert multiple biological effects on tumor cell behaviour, in vitro. Cancer patients with high levels of proteinase inhibitors are often characterized by a more disseminated disease and worse prognosis. We have found that plasma levels of AAT, alpha1-antichymotrypsin and secreted leukocyte proteinase inhibitor are significantly higher in newly diagnosed lung cancer patients, particularly in cases with metastases, compared to the age and gender matched controls. These results support the view that proteinase inhibitor levels may reflect or contribute to tumor progression. We next examined the effects of inhibitory (native) and non-inhibitory (polymerized and/or C-terminal fragment, C-36) forms of AAT on human neutrophil and lung cancer cell functional activities separately and in co-culture models, in vitro. Our data show that the C-36 peptide of AAT, in a concentration-dependent manner, induces neutrophil chemotaxis, adhesion, degranulation and superoxide generation, while native and polymerized AAT at similar and higher concentrations were without effect. In co-culture experiments we observed that interactions between neutrophil released content and lung cancer cells were modulated by exogenously added AAT and C-36 peptide. Similar experiments performed in vitro on lung, breast and pancreatic cancer cells showed that AAT, depending on its molecular form, may either promote or inhibit cancer cell proliferation, invasiveness and the ability to release certain biomarkers, such as growth factors, cytokines and matrix metalloproteinases. Together our findings support the hypothesis that AAT’s role in cancer progression might not only be limited to its property of inhibiting overexpressed proteinases but also to direct effects on inflammatory and tumor cells. (Less)
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author
opponent
  • Kalsheker, Noor, Co-Director of the Institute of Genetics
organization
publishing date
type
Thesis
publication status
published
subject
keywords
cancer, onkologi, Cytologi, cancerology, oncology, Cytology, invasion, neutrophils, cancer cell, Alpha1- antitrypsin, proteinase inhibitors
pages
165 pages
publisher
Zelvyte Inga, Vikensvagen 73B, Hollviken 23461,
defense location
Aula, Entrance 35, 1st floor, Malmo University Hospital
defense date
2004-04-16 13:15
ISBN
91-628-6031-3
language
English
LU publication?
yes
id
5a8ec799-6302-406b-ace3-4fe0d44ad9ce (old id 466773)
date added to LUP
2007-09-26 17:05:33
date last changed
2016-09-19 08:45:04
@misc{5a8ec799-6302-406b-ace3-4fe0d44ad9ce,
  abstract     = {Alpha1-antitrypsin (AAT), a circulating single-chain glycoprotein is the most abundant serine proteinase inhibitor in human plasma. AAT is an acute phase protein, its levels increase rapidly to concentrations exceeding 50mM in response to inflammation, infection and malignant diseases. Since AAT is a powerful inhibitor of neutrophil elastase and proteinase 3, it is generally assumed that its physiological function is to protect host tissue from the proteolytic actions of these proteinases. However, in vivo AAT is found not only in the native, inhibitory form, but also modified non-inhibitory forms including polymerized, cleaved and/or degraded. Recent findings suggest that non-inhibitory forms of AAT may also express biological activity, un-related to serine proteinase inhibition. The overall aim of the studies upon which this thesis is based was to test a hypothesis that AAT in native and modified molecular forms may exert multiple biological effects on tumor cell behaviour, in vitro. Cancer patients with high levels of proteinase inhibitors are often characterized by a more disseminated disease and worse prognosis. We have found that plasma levels of AAT, alpha1-antichymotrypsin and secreted leukocyte proteinase inhibitor are significantly higher in newly diagnosed lung cancer patients, particularly in cases with metastases, compared to the age and gender matched controls. These results support the view that proteinase inhibitor levels may reflect or contribute to tumor progression. We next examined the effects of inhibitory (native) and non-inhibitory (polymerized and/or C-terminal fragment, C-36) forms of AAT on human neutrophil and lung cancer cell functional activities separately and in co-culture models, in vitro. Our data show that the C-36 peptide of AAT, in a concentration-dependent manner, induces neutrophil chemotaxis, adhesion, degranulation and superoxide generation, while native and polymerized AAT at similar and higher concentrations were without effect. In co-culture experiments we observed that interactions between neutrophil released content and lung cancer cells were modulated by exogenously added AAT and C-36 peptide. Similar experiments performed in vitro on lung, breast and pancreatic cancer cells showed that AAT, depending on its molecular form, may either promote or inhibit cancer cell proliferation, invasiveness and the ability to release certain biomarkers, such as growth factors, cytokines and matrix metalloproteinases. Together our findings support the hypothesis that AAT’s role in cancer progression might not only be limited to its property of inhibiting overexpressed proteinases but also to direct effects on inflammatory and tumor cells.},
  author       = {Zelvyté, Inga},
  isbn         = {91-628-6031-3},
  keyword      = {cancer,onkologi,Cytologi,cancerology,oncology,Cytology,invasion,neutrophils,cancer cell,Alpha1- antitrypsin,proteinase inhibitors},
  language     = {eng},
  pages        = {165},
  publisher    = {ARRAY(0xab24148)},
  title        = {Alpha 1-antitrypsin: A Role in Cancer Progression},
  year         = {2004},
}