Development of laboratory models to study Breast Cancer
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Transcript of Development of laboratory models to study Breast Cancer
Development of laboratory Development of laboratory models to study Breast Cancermodels to study Breast Cancer
Deborah Holliday
Breast Research GroupSection of Pathology & Tumour Biology
Section of Pathology and Tumour Biology
OutlineOutline
Introduction to the cells found in breast tissue
Changes in breast cells during breast cancer
Designing a model of breast cancermethods
Use of the model: A tool for looking at cancer progression
Cellular components of the normal breastCellular components of the normal breast
Luminal epithelial cells: Milk producing cells Hormone responsive ER-alpha positive cells
Myoepithelial cells: Surround the luminal cells Contractile cells
Luminal and Myoepithelial cells form the glandular unit of the breast
Fibroblasts: Form the structural component of the surrounding breast
tissue Produce proteins important for maintaining breast structure
Other cell types Blood vessels, fat cells, inflammatory cells
Fibroblasts
Myoepithelialcells
Tumourcells
Luminal cells
Normal breast tissue
Cells look ordered in appearance
Pre-invasive breast cancer Tumour cells in the centre start to grow out of control
Invasive breast cancer Tumour cells escape into the surrounding breast tissueOrdered structure of the tissue is lost
Breast Cancer ProgressionBreast Cancer Progression
Pre-invasive breast cancer: Ductal Pre-invasive breast cancer: Ductal carcinoma in situcarcinoma in situ (DCIS)(DCIS)
DCIS is characterised by confinement of tumour cells to the breast glandular unit
DCIS accounts for 40% of screen detected breast carcinoma
25-30% of untreated DCIS will progress to invasive carcinoma
Problems with treatment of DCISProblems with treatment of DCIS
Mastectomy Patient is cured but ? Overtreatment ?
Conservative surgery A proportion of tumours will recur Some of those will progress to invasive
carcinoma
Important to define which DCIS cases Important to define which DCIS cases are likely to progressare likely to progressA better understanding of the biology A better understanding of the biology of tumour invasion may reveal new of tumour invasion may reveal new targets for therapiestargets for therapies
Designing a human model of breast cancerDesigning a human model of breast cancer
The model would need to include 3 major cell types involved in breast cancer: Tumour cells. Myoepithelial cells (protector cells). Fibroblasts (tumour helper cells).
Cells would need to be grown in culture conditions which resemble those in the body: Able to grow in 3 dimensions rather than on a plastic Petri
dish.
Such a model would be a valuable tool:
To help us understand how breast cancer progresses. To allow us to test new drugs for therapy. To potentially identify new targets for future drug
development.
MethodsMethods
We isolated cells from normal breast tissue or from breast cancer tissue and grew then in a 3 dimensional matrix of collagen. By labelling our cells with different colours we were able to identify the different cell types in our model. We used the model to investigate whether fibroblasts are able to make pre-invasive lesions become invasive.
Luminal cells
Fibroblasts
Collagen I
Culture media
Myoepithelialcells
Results
F
B
Day 1 Day 3 Day 5 Day 7
Blue: Tumour cells Red: Myoepithelial cells Green: Normal Fibroblasts
Green: Tumour Fibroblasts
Ductal carcinoma in situ (DCIS)
Invasive breast Carcinoma
Quantifying the modelQuantifying the model
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lum/myo/Nfib mcf/myo/TAF
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Normal Fibroblasts
Tumour Fibroblasts
Normal Fibroblasts
Tumour Fibroblasts
How we are using the model
• Different tumour cells to represent different types of breast cancer• Different fibroblasts to understand why in some patients cancer
progresses faster than in others• Include drugs into the model with tumour fibroblasts to see if we can
prevent ‘invasion’– Established drugs – New Drugs = pre-clinical drug screen
• We have a model which we can use to study the biology of breast cancer
• This will help us understand how breast cancer progresses
Summary
Using 3D models to study radio-Using 3D models to study radio-resistance in Breast Cancerresistance in Breast Cancer
Laura Smith
Breast Research GroupSection of Pathology & Tumour Biology
Section of Pathology and Tumour Biology
Outline
Radiotherapy
Issues with radiotherapy
What would help overcome these issues?
The use of 3D models
Radiotherapy
Reduces risk of the cancer coming back
Is given to many breast cancer patients All patients having breast conserving
surgery
Patients having a mastectomy but at high risk of the cancer coming back
Issues with Radiotherapy
Unpleasant side effects Short term Long term
Stressful regime Daily hospital visits 5 days/ week for 3
weeks Limited availability of treatment
machines Long waiting lists in some areas
Not all patients will benefit Some patients cancer will come back
anyway
Overcoming these issues Better patient selection
Estrogen Receptor for Tamoxifen therapy HER2 for Herceptin therapy Nothing analogous to guide radiotherapy
Why do some cancers respond well to radiotherapy whilst others do not?
What factors are involved? Radio-sensitizing drugs?
Our Study
It is not only cancer cells that are exposed to radiotherapy but also the fibroblasts
Do fibroblasts influence breast cancer cell response to radiotherapy?
Do fibroblasts differentially influence the response of different breast cancer types?
Luminal cells
Treated Fibroblasts
Collagen I
Culture media
Myoepithelialcells
Use of 3D Models
Luminal cells
Untreated Fibroblasts
Collagen I
Culture media
Myoepithelialcells
Luminal cells Type II
Treated Fibroblasts
Collagen I
Culture media
Myoepithelialcells
Luminal cells Type I
Treated Fibroblasts
Collagen I
Culture media
Myoepithelialcells
Use of 3D Models
Summary
Reduce side effects and improve quality of life for patients that will not benefit
Allow drs to select another type of treatment that will work for these patients
Reduce waiting times for those patients that will benefit thereby increasing survival