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Mechanisms Involved in Cartilage Oligomeric Matrix Protein’s (COMP) Generation of Cancer Stem Cells and Protection Towards Stress Signals in Breast Cancer

Rodriguez-Cupello, Carmen (2018) MOBN03 20172
Degree Projects in Molecular Biology
Popular Abstract
Cartilage Oligomeric Matrix Protein and the Generation of Cancer Stem Cells

Cartilage Oligomeric Matrix Protein (COMP) is a pentameric molecule normally found in cartilage and bone tissue. No known link between COMP and cancer had been found before the original investigation. Elevated levels of COMP in breast tumor cells was correlated with decreased survival and increased recurrence of the disease. It was also found that the Notch pathway was one of the many dysregulated by elevated COMP levels in cells (Englund et al. 2016). The mechanism by which COMP affects and enhances the Notch pathway was investigated to determine the effects and the relation to initiation of cancer stem cells.

Through immunofluorescent staining,... (More)
Cartilage Oligomeric Matrix Protein and the Generation of Cancer Stem Cells

Cartilage Oligomeric Matrix Protein (COMP) is a pentameric molecule normally found in cartilage and bone tissue. No known link between COMP and cancer had been found before the original investigation. Elevated levels of COMP in breast tumor cells was correlated with decreased survival and increased recurrence of the disease. It was also found that the Notch pathway was one of the many dysregulated by elevated COMP levels in cells (Englund et al. 2016). The mechanism by which COMP affects and enhances the Notch pathway was investigated to determine the effects and the relation to initiation of cancer stem cells.

Through immunofluorescent staining, co-immunoprecipitation, and ELISA, we were able to show that COMP is able to interact with the receptor Notch 3 and its ligand Jagged 1. This interaction leads to the generation of a larger stem cell population in COMP expressing cells, viewed through ALDH+ population, increased CD133 cell surface marker, and increased tumor sphere formation which was verified in vivo in mice with varying COMP levels (Figure 1). We were also able to show that activated Notch 3 can interact with other cell fate determining pathways like Wnt and Akt, which could enhance this effect.

Delving further, we looked at the role of COMP’s domains in the role of generation of cancer stem cells. While the results of these experiments varied greatly, we were able to show that the thrombospondin region is crucial for the generation of tumor spheres in COMP expressing cells (Figure 2). The thrombospondin domain was also shown to interact/affect with the Akt pathway. While COMP has also been shown to be resistive to apoptotic signals, the thrombospondin region was found to not be responsible for this.

In conclusion, we were able to show that COMP enhances the interaction between Notch 3 and Jagged 1, leading to increased activation of Notch 3 and the generation of cancer stem cells. The increased quantity of cancer stem cells is detrimental to patients, allowing for the cancer to relapse. Determining a mechanism to inhibit this elevated activation without inhibiting the normal functions of these proteins is crucial for potential therapies for the roughly 20% of breast cancer patients with elevated COMP levels.

Master’s Degree Project in Molecular Biology - 60 Credits
Department of Biology, Lund University

Advisors: Anna Blom and Konstantinos Papadakos
Department of Translational Medicine, Lund University (Less)
Please use this url to cite or link to this publication:
author
Rodriguez-Cupello, Carmen
supervisor
organization
course
MOBN03 20172
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
8952592
date added to LUP
2018-06-25 08:59:12
date last changed
2018-06-25 08:59:12
@misc{8952592,
  author       = {{Rodriguez-Cupello, Carmen}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Mechanisms Involved in Cartilage Oligomeric Matrix Protein’s (COMP) Generation of Cancer Stem Cells and Protection Towards Stress Signals in Breast Cancer}},
  year         = {{2018}},
}