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Proliferation, Invasion and p16 Localisation in Malignancies

Nilsson, Kristina LU (2006) In Lund University Faculty of Medicine Doctoral Dissertation Series
Abstract
Uncontrolled proliferation and invasion are two characteristics in tumour development and progression. Previous studies have shown that invading tumour cells in colorectal cancer have low proliferation in parallel to upregulation of the tumour suppressor p16. We set out to detail the p16 expression and proliferation in basal cell carcinoma and squamous cell carcinoma of the skin, tumours that are locally infiltrative and aggressive. p16 was upregulated at the invasive margin compared to central parts in both tumours, and in basal cell carcinoma there was also a decreased proliferation in infiltrating p16 high tumour cells. In squamous cell carcinoma the Rb-pathway was non-functional, probably due to inactivation of Rb or a de-localisation... (More)
Uncontrolled proliferation and invasion are two characteristics in tumour development and progression. Previous studies have shown that invading tumour cells in colorectal cancer have low proliferation in parallel to upregulation of the tumour suppressor p16. We set out to detail the p16 expression and proliferation in basal cell carcinoma and squamous cell carcinoma of the skin, tumours that are locally infiltrative and aggressive. p16 was upregulated at the invasive margin compared to central parts in both tumours, and in basal cell carcinoma there was also a decreased proliferation in infiltrating p16 high tumour cells. In squamous cell carcinoma the Rb-pathway was non-functional, probably due to inactivation of Rb or a de-localisation of p16 to the cytoplasm, and p16 could consequently not inhibit proliferation in infiltrating cells. In contrast to the malignant skin tumours, p16 was commonly expressed in central parts of the tumour islands in cylindroma, and in this benign slow growing tumour p16 seemed important in restraining the proliferative activity of the tumour cells. Further, by subcellular fractionation we confirmed that p16 was expressed in both the nucleus and in the cytoplasm in tumour cell lines, and the protein could bind to cdk4/6 in both subcellular compartments, even if it seemed incapable of inhibiting proliferation. Investigating post-translational modifications of p16 revealed at least two forms of p16 in cell lines, as well as in skin tumours. We further investigated the relation between tumour cell proliferation and migration in a breast cancer cell line and observed that resting cells were more migratory than actively cycling cells. This was also confirmed in a cohort of primary breast tumours, where proliferation and infiltrative growth pattern were inversely correlated. However, the actively cycling breast tumour cells could be rendered more migratory upon exposure to macrophage like stimuli. Thus, in some tumour cells, proliferation and invasion/migration seem to be contrasting events. However, in other tumours, potentially with more severe aberrations in cell cycle regulatory pathways, the cells can proliferate and migrate concurrently. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Okontrollerad proliferation och invasion är två viktiga egenskaper i tumörutveckling och tumörprogression. Tidigare studier har visat att invaderande tumörceller i kolorektalcancer har låg proliferation parallellt med en uppreglering av tumörsuppressorn p16. Vi undersökte p16-uttrycket och proliferation i basalcellscancer och skivepitelcancer i huden, tumörer som är lokalt infiltrativa och aggressiva. p16 var uppreglerat i invasiva celler jämfört med celler i centrala delar i båda tumörerna, och i basalcellscancer fann vi en minskad proliferation i celler med högt p16-uttryck. I skivepitelcancer var Rb-vägen inte funktionell, troligtvis genom inaktivering av Rb, eller genom en de-lokalisering av... (More)
Popular Abstract in Swedish

Okontrollerad proliferation och invasion är två viktiga egenskaper i tumörutveckling och tumörprogression. Tidigare studier har visat att invaderande tumörceller i kolorektalcancer har låg proliferation parallellt med en uppreglering av tumörsuppressorn p16. Vi undersökte p16-uttrycket och proliferation i basalcellscancer och skivepitelcancer i huden, tumörer som är lokalt infiltrativa och aggressiva. p16 var uppreglerat i invasiva celler jämfört med celler i centrala delar i båda tumörerna, och i basalcellscancer fann vi en minskad proliferation i celler med högt p16-uttryck. I skivepitelcancer var Rb-vägen inte funktionell, troligtvis genom inaktivering av Rb, eller genom en de-lokalisering av p16 till cytoplasman, varpå p16 inte kunde inhibera proliferation i de infiltrerande cellerna. Till skillnad mot i de maligna hudtumörerna uttrycktes p16 centralt i tumöröarna i cylindrom, och i denna benigna långsamtväxande hudtumör tycktes p16 viktig för att inhibera proliferationen. Vidare visade vi, genom subcellulär fraktionering, att p16 uttrycktes i både kärnan och cytoplasman i vissa tumörcellinjer, och att proteinet kunde binda till cdk4/6 på båda ställena, även om det inte kan inhibera proliferationen. När vi undersökte post-translationella modifieringar av p16 fann vi minst två former av p16 i tumörcellinjer och i hudtumörer. Vi undersökte vidare förhållandet mellan tumörcellsproliferation och migration i en bröstcancercellinje och fann att vilande celler var mer migratoriska än aktivt delande celler. Detta verifierades dessutom i primära brösttumörer där vi fann ett inverst förhållande mellan proliferation och infiltrativt växtsätt. Dock kunde de aktivt delande cellerna bli mer migratoriska vid exponering för ett makrofagliknande stimulus. Sammanfattningsvis tycks proliferation och invasion/migration inte ske samtidigt i vissa tumörceller. I andra tumörer, möjligtvis med större fel i cellcykelregulatoriska vägar, kan cellerna däremot proliferera och migrera samtidigt. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Åman, Pierre, Department of Pathology, the Gothenburg University, Sahlgrenska University Hospital, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
onkologi, Cytologi, cancerology, Cytology, oncology, skin tumours, invasion, p16, cancer, patologisk anatomi, Patologi (allmän), pathological anatomy, proliferation, General pathology
in
Lund University Faculty of Medicine Doctoral Dissertation Series
pages
107 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Main lecture hall, Pathology building entrance 78, Malmö University Hospital, Malmö
defense date
2006-11-24 09:00:00
ISSN
1652-8220
ISBN
91-85559-51-2
language
English
LU publication?
yes
additional info
Sofie Svensson, Kristina Nilsson, Anita Ringberg and Göran Landberg. 2003. Invade or Proliferate? Two contrasting events in malignant behavior governed by p16INK4a and an intact Rb pathway illustrated by a model system of basal cell carcinoma Cancer Research, pp 1737-1742. American Association for Cancer Research
Kristina Nilsson, Sofie Svensson and Göran Landberg. 2004. Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior Modern Pathology, pp 1464-1474. United States and Canadian Academy of Pathology, Inc.
Kristina Nilsson and Göran Landberg. 2006. Subcellular localization, modification and protein complex formation of the cdk-inhibitor p16 in Rb-functional and Rb-inactivated tumor cells International Journal of Cancer, pp 1120-1125. Wiley-Liss, Inc.
Kristina Nilsson, Otto Ljungberg and Göran Landberg. . The Cyld-/-, cyclin D1 driven tumor, cylindroma, has limited proliferation due to upregulation of the tumor suppressor p16 (manuscript)
Pontus Berglund, Kristina Nilsson, Karin Jirström, Sofie Svensson Månsson and Göran Landberg. . Proliferation and migration are contrasting and coordinated events in breast cancer, and are partially regulated via Erk1/2-activation (manuscript)
id
bdd0f973-ea1c-4486-bf8c-3b079f58a8cf (old id 547531)
date added to LUP
2016-04-01 16:20:11
date last changed
2019-05-22 05:55:27
@phdthesis{bdd0f973-ea1c-4486-bf8c-3b079f58a8cf,
  abstract     = {{Uncontrolled proliferation and invasion are two characteristics in tumour development and progression. Previous studies have shown that invading tumour cells in colorectal cancer have low proliferation in parallel to upregulation of the tumour suppressor p16. We set out to detail the p16 expression and proliferation in basal cell carcinoma and squamous cell carcinoma of the skin, tumours that are locally infiltrative and aggressive. p16 was upregulated at the invasive margin compared to central parts in both tumours, and in basal cell carcinoma there was also a decreased proliferation in infiltrating p16 high tumour cells. In squamous cell carcinoma the Rb-pathway was non-functional, probably due to inactivation of Rb or a de-localisation of p16 to the cytoplasm, and p16 could consequently not inhibit proliferation in infiltrating cells. In contrast to the malignant skin tumours, p16 was commonly expressed in central parts of the tumour islands in cylindroma, and in this benign slow growing tumour p16 seemed important in restraining the proliferative activity of the tumour cells. Further, by subcellular fractionation we confirmed that p16 was expressed in both the nucleus and in the cytoplasm in tumour cell lines, and the protein could bind to cdk4/6 in both subcellular compartments, even if it seemed incapable of inhibiting proliferation. Investigating post-translational modifications of p16 revealed at least two forms of p16 in cell lines, as well as in skin tumours. We further investigated the relation between tumour cell proliferation and migration in a breast cancer cell line and observed that resting cells were more migratory than actively cycling cells. This was also confirmed in a cohort of primary breast tumours, where proliferation and infiltrative growth pattern were inversely correlated. However, the actively cycling breast tumour cells could be rendered more migratory upon exposure to macrophage like stimuli. Thus, in some tumour cells, proliferation and invasion/migration seem to be contrasting events. However, in other tumours, potentially with more severe aberrations in cell cycle regulatory pathways, the cells can proliferate and migrate concurrently.}},
  author       = {{Nilsson, Kristina}},
  isbn         = {{91-85559-51-2}},
  issn         = {{1652-8220}},
  keywords     = {{onkologi; Cytologi; cancerology; Cytology; oncology; skin tumours; invasion; p16; cancer; patologisk anatomi; Patologi (allmän); pathological anatomy; proliferation; General pathology}},
  language     = {{eng}},
  publisher    = {{Department of Laboratory Medicine, Lund University}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Proliferation, Invasion and p16 Localisation in Malignancies}},
  year         = {{2006}},
}