Invasion and Proliferation in Malignant Cells

Sofie Svensson Månsson

Research output: ThesisDoctoral Thesis (compilation)

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Abstract

Two key events in the oncogenic process of tumor cells are to acquire uncontrolled proliferation and invasive properties. This allows the tumor to grow and invade beyond the tissue from which the tumor cells originate. We here specifically studied p16 and ERK1/2 with special focus on and the relation to proliferation and invasion in non-melanoma skin cancer and in breast cancer.

In a model system of basal cell carcinoma, we observed that tumor cells changed phenotype from a highly proliferative type in the centre of the tumor to an invasive type with low proliferation and a marked upregulation of p16 at the invasive front. The expression of p16 was transcriptionally regulated and possible p16 activators such as ERK1/2 or Ets were not the sole contributors. Similar findings were observed in squamous cell carcinoma of the skin, despite a non functional Rb pathway, which might indicate a proliferation independent role for p16 in invasive behaviors.

In primary breast cancer, a signaling cascade from VEGFR2 via ERK1/2 phosphorylation to Ets2 phosphorylation and cyclin D1, could be outlined and ERK1/2 phosphorylation was linked to small tumors with good prognosis. We also observed a Notch1 independent activation of Hes1 in breast cancer. Further, postmenopausal patients with ERK1/2 phosphorylated tumors had an impaired tamoxifen response, but ERK1/2 phosphorylation was not linked to tamoxifen resistance in premenopausal women.

Taken together, our results implicate that there is a general inverse association between invasion and proliferation in some malignancies and this novel finding could be important when designing new treatment strategies for cancer patients.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Pathology, Malmö
Supervisors/Advisors
  • Landberg, Göran, Supervisor
Award date2006 Oct 27
Publisher
Print ISBNs91-85559-35-0
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-10-27
Time: 09:00
Place: Main Lecture Hall, Pathology building entrance 78, Malmö University Hospital, Malmö, Sweden

External reviewer(s)

Name: Berx, Geert
Title: Dr.
Affiliation: Ghent University, Belgium

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<div class="article_info">S Svensson, K Nilsson, A Ringberg and G Landberg. <span class="article_issue_date">2003</span>. <span class="article_title">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.</span> <span class="journal_series_title">Cancer Research</span>, <span class="journal_volume">vol 63</span> <span class="journal_pages">pp 1737-1742</span>.</div>
<div class="article_info">K Nilsson, S Svensson and G Landberg. <span class="article_issue_date">2004</span>. <span class="article_title">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.</span> <span class="journal_series_title">Modern Pathology</span>, <span class="journal_volume">vol 17</span> <span class="journal_pages">pp 1464-1474</span>.</div>
<div class="article_info">S Svensson Månsson, J S Reis Filho and G Landberg. <span class="article_issue_date"></span>. <span class="article_title">Transcriptional upregulation and unmethylation of the promoter region of p16 in invasive basal cell carcinoma cells and partial co-localisation with the ÿ2 subunit of laminin-5.</span> (manuscript)</div>
<div class="article_info">S Svensson, K Jirström, L Ryden, G Roos, S Emdin, MC Ostrowski and G Landberg. <span class="article_issue_date">2005</span>. <span class="article_title">ERK1/2 phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis.</span> <span class="journal_series_title">Oncogene</span>, <span class="journal_volume">vol 24</span> <span class="journal_pages">pp 4370-4379</span>.</div>
<div class="article_info">S Svensson Månsson, C Manetopoulos, M E Johansson, L Ryden, K Jirström, G Landberg and H Axelsson. <span class="article_issue_date"></span>. <span class="article_title">Association between the ERK pathway and the Notch target gene Hes1 in primary breast cancer and in breast cancer cell lines.</span> (manuscript)</div>

Subject classification (UKÄ)

  • Cancer and Oncology
  • Cell and Molecular Biology

Keywords

  • cancerology
  • oncology
  • Cytology
  • breast cancer
  • squamous cell carcinoma
  • basal cell carcinoma
  • p16
  • proliferation
  • invasion
  • Cytologi
  • onkologi
  • cancer

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