Origin and Function of the Stroma in Cholangiocarcinoma
Lead Research Organisation:
University of Edinburgh
Department Name: MRC Centre for Inflammation Research
Abstract
The bile duct is a tube that connects the liver to the intestines. It delivers the waste products of the liver to the gut. Cancer of the bile duct (cholangiocarcinoma) is rarely curable, has a poor survival and is increasingly common worldwide. We aim to study the role that the body’s own immune cells (such as macrophages) play in cholangiocarcinoma.
There is evidence that macrophages can increase tumour cell growth in certain situations. Cholangiocarcinoma tumours are surrounded by these cells and we are trying to discover whether these may be important in the development of this cancer.
We aim to investigate the relationship between the cancer cells and immune cells. This may eventually result in the development of novel treatments for this cancer.
There is evidence that macrophages can increase tumour cell growth in certain situations. Cholangiocarcinoma tumours are surrounded by these cells and we are trying to discover whether these may be important in the development of this cancer.
We aim to investigate the relationship between the cancer cells and immune cells. This may eventually result in the development of novel treatments for this cancer.
Technical Summary
Background
Cholangiocarcinoma (CC) is the second commonest primary liver malignancy. The worldwide incidence of CC is increasing rapidly and the prognosis is dismal. Chemotherapy is ineffective; very few patients are candidates for surgery. Even for resectable lesions the 5-year survival rates are at best 30-40% for hilar lesions and 22-36% for intrahepatic CC.
Relevance
Inflammation, from a variety of causes, is a strong risk factor for CC. Intrahepatic CC is characterised by a pronounced desmoplastic response (stroma) consisting primarily of macrophages, myofibroblasts and extra-cellular matrix. The stromal components of cancers have been shown to promote invasiveness, tumour survival and resistance to therapy. In a number of tumours a proportion of the cancer-associated stroma is derived from Bone Marrow (BM).
A variety of signalling molecules, including Notch, have been implicated in the progression of CC. Manipulating the stromal component of CC may provide novel therapeutic options.
Aims and Objectives
To define the origin and functional role of the stroma in CC by:
1) Defining the composition and origin of CC associated stroma during the formation of CC.
2) Performing functional analyses of the stromal cell-CC interaction.
Design and Methodology
1. Perform BM transplants prior to cancer induction in a model of CC development to define the composition and origin of the cancer associated stroma.
2. Deplete macrophages and myofibroblasts in independent validated protocols during CC development and analyse the functional relationship between the stroma and the CC.
3. Carry out in vitro culture studies of CC and stromal cells to analyse the stromal cell-CC interaction. Studies of CC cell behaviour in response to soluble factors and extra-cellular matrix components will be performed. The role of specific signalling molecules, including Notch, will be assessed.
Scientific and Medical opportunities of the study
To date the treatment options for cholangiocarcinoma are limited and chemotherapy directed at the CC cells is largely ineffective. We believe this study will define the origin, composition and functional role of the CC associated stroma- including a definition of the specific signals that mediate the growth promoting and chemo-protective effects of the stroma. This may enable the future development of specific therapies for the treatment of CC that may target either the stroma or the stroma-CC interaction.
Cholangiocarcinoma (CC) is the second commonest primary liver malignancy. The worldwide incidence of CC is increasing rapidly and the prognosis is dismal. Chemotherapy is ineffective; very few patients are candidates for surgery. Even for resectable lesions the 5-year survival rates are at best 30-40% for hilar lesions and 22-36% for intrahepatic CC.
Relevance
Inflammation, from a variety of causes, is a strong risk factor for CC. Intrahepatic CC is characterised by a pronounced desmoplastic response (stroma) consisting primarily of macrophages, myofibroblasts and extra-cellular matrix. The stromal components of cancers have been shown to promote invasiveness, tumour survival and resistance to therapy. In a number of tumours a proportion of the cancer-associated stroma is derived from Bone Marrow (BM).
A variety of signalling molecules, including Notch, have been implicated in the progression of CC. Manipulating the stromal component of CC may provide novel therapeutic options.
Aims and Objectives
To define the origin and functional role of the stroma in CC by:
1) Defining the composition and origin of CC associated stroma during the formation of CC.
2) Performing functional analyses of the stromal cell-CC interaction.
Design and Methodology
1. Perform BM transplants prior to cancer induction in a model of CC development to define the composition and origin of the cancer associated stroma.
2. Deplete macrophages and myofibroblasts in independent validated protocols during CC development and analyse the functional relationship between the stroma and the CC.
3. Carry out in vitro culture studies of CC and stromal cells to analyse the stromal cell-CC interaction. Studies of CC cell behaviour in response to soluble factors and extra-cellular matrix components will be performed. The role of specific signalling molecules, including Notch, will be assessed.
Scientific and Medical opportunities of the study
To date the treatment options for cholangiocarcinoma are limited and chemotherapy directed at the CC cells is largely ineffective. We believe this study will define the origin, composition and functional role of the CC associated stroma- including a definition of the specific signals that mediate the growth promoting and chemo-protective effects of the stroma. This may enable the future development of specific therapies for the treatment of CC that may target either the stroma or the stroma-CC interaction.
