Final Report Summary - INFLA-CARE (Understanding inflammation-associated tumorigenesis for the rational design of novel anti-cancer therapeutic strategies.)
Executive Summary:
Epidemiological and experimental evidence supports a link between chronic inflammation and cancer and indicates a role for inflammatory cells in the initiation, progression and metastasis of malignancy. The collaborative integrated project INFLA-CARE has established a European network of scientific and technological excellence in the field of ‘Inflammation & Cancer’ which capitalises on the available expertise with a view to develop effective anti-inflammatory strategies and novel agents or screening platforms for cancer prevention and treatment.
The project has specifically sought to identify molecular and cellular targets for cancer therapy through the development and systematic study of state-of-the-art pre-clinical models of inflammation-driven cancer. During the period of the grant, INFLA-CARE researchers have developed and utilised a variety of in vitro and in vivo models to study the role of cytokines and pro-inflammatory signalling mediators in lung, liver and colorectal carcinogenesis and analyse the molecular pathways involved, including the NF-B and MAPK cascades. The consortium has also discovered novel links between ageing, obesity and inflammation which may impact on carcinogenesis.
By mobilising the outstanding research experience and technological capacities of the network participants, the program has identified and tested new diagnostic and therapeutic strategies which are expected to lead to improved detection, prevention and management of several types of human cancer. It has also discovered novel interactions between the immune system and the response to chemotherapy which will enrich the oncological armamentarium towards ‘patient-tailored’ therapies. These studies have overall yielded significant results which provided the basis for the rational design of novel therapeutic strategies. Procedures and platforms have also been established for the analysis and further evaluation of data that have been generated, including bio-computing software for data integration and concept discovery.
In addition to its major scientific contributions, INFLA-CARE has worked to ensure spreading of scientific excellence and dissemination of knowledge beyond the network, by encouraging innovation and transfer of knowledge and by raising public understanding of scientific and health issues.
Project Context and Objectives:
Dunn and colleagues proposed in 2004 that the relationship between the immune response and tumorigenesis is characterized by 3 stages, collectively called immunoediting. The first stage, termed elimination, represents the period in which the immune system, through successful immunosurveillance, destroys precancerous and cancerous cells. In equilibrium, the second stage, cancer cells have begun to develop capabilities to overcome immunosurveillance but the balance between “immune patrol” and tumorigenesis is still preserved. In the third stage, named escape, the cancer cells manage to override the immune response, resulting in aberrant cell proliferation and tumor development.
The significance of immunoediting in carcinogenesis is highlighted by a seminal paper published in Science by a team of scientists which includes INFLA-CARE researchers, showing that chromosomal content in a tumor is controlled indirectly by an immunosurveillance mechanism which ensures the elimination of hyperploid cells. In particular, this work demonstrated that hyperploid cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin. CRT facilitates the phagocytosis of stressed and dying cells by macrophages as well as by antigen-presenting dendritic cells and it thus part of a barrier mechanism to restrain tumor growth.
On the other hand, the powerful impact of immune cells on cancer has been recognised for many years. Epidemiological studies indicate that approximately 15% of all malignancies can be attributed to infectious agents, such as viruses and bacteria that are able to evade clearance by the immune system and establish a state of chronic inflammatory imbalance. Chronic inflammation has, however, a much broader role in the pathogenesis of cancer. Indeed, experimental and clinical evidence suggests that sustained (and frequently sub-clinical) inflammation triggered by chronic exposure to toxic agents, irritants, oncogenes or autoimmune reactions may contribute to the initiation, progression and metastasis of diverse types of human cancer, including lung, colon and breast.
Inflammatory bowel disease is probably the best-known chronic inflammatory disorder which pre-disposes to cancer and includes Crohn’s disease and ulcerative colitis. Tumorigenesis in colitis-associated cancer (CAC) is thought to evolve via heterotypic interactions between cancer cells, bacteria flora and multiple recruited or resident stromal cell types forming the tumor microenvironment. A stromal component of particular importance to tumorigenesis, especially in CAC, has been the inflammatory component, which appears to promote the neoplastic potential of intestinal epithelial cells (IECs) via the production of proinflammatory cytokines and chemokines, proangiogenic and growth factors, ROS, and proinvasive matrix-degrading proteases. However, the specific signaling pathways underlying inflammatory cell recruitment and their effector functions during tumorigenesis are not fully understood and relatively little is known about the molecular mechanisms mediating resident stromal cell activation and crosstalk with the adjacent tumor epithelium and its microenvironment.
Hepatocellular carcinoma (HCC) is another disease largely attributed to chronic inflammation. HCC is rapidly increasing globally and is now the 4th major cancer killer in men. Present treatments are limited and prognosis upon diagnosis is bleak unless the patient is suitable for an available liver transplantation. There is growing evidence for a disease axis involving interplay between inflammatory, fibrogenic and tumourogenic processes in the diseased liver. The links between liver inflammation and fibrosis are well established and at least 90% of cases of hepatocellular carcinoma develop on the background of severe fibrosis. However, mechanisms are less well established although there is growing evidence that the main fibrogenic cell of the liver, the hepatic stellate cell-derived myofibroblast, contributes to tumour growth by generating a microenvironment that is favourable to tumour growth and survival. In particular the hepatic myofibroblast contributes stable collagen-rich extracellular matrix and a soup of pro-inflammatory molecules that act as growth factors for tumour cells.
Lung cancer is the most common cause of cancer-related deaths in the western world. The recent EUROCARE 3 study has showed that more than 230,000 people in the EU died of lung cancer in 2000, that is one in five of all deaths from cancer. A major risk factor for this type of malignancy is the excessive exposure to chemical carcinogens and particles in tobacco smoke which cause genomic instability and low level, often subclinical, chronic inflammation. There is also an established link between chronic inflammation caused by silica (silicosis) or bacterial infections and lung carcinoma6.
Current treatments for cancer include primary tumour resection and/or aggressive radiotherapy and chemotherapy to achieve both local control and therapy for distant metastases. Conventional cancer treatments are therefore designed to target malignant cells. Tumors, however, frequently develop resistance to therapy as a consequence of the multiple genetic and epigenetic changes they accumulate. Drug resistance represents a major clinical problem and cause of mortality among cancer patients and largely accounts for the limited success of the conventional anti-cancer strategies. Targeting the inflammatory, non-transformed component of tumors may therefore offer an attractive alternative for both the prevention and treatment of malignant disease.
This alternative concept for combating cancer represents the core of the research and technological activities of the collaborative integrated project INFLA-CARE. Through the mobilisation of the research expertise and technological capacities of the INFLA-CARE network participants, we have sought to translate the knowledge of the molecular pathways regulating inflammation-driven cancer into new diagnostic and therapeutic strategies which will be used for the detection, prevention and improved management of several types of human cancer.
The development of such novel approaches to fight cancer has been so far impeded by the near absence of concerted trans-disciplinary collaborative efforts which could rigorously define the influence of the inflammatory microenvironment on tumor growth and, in particular, identify the early molecular events that trigger tumor initiation in chronic inflammatory sites. Technological limitations have also precluded the use of microarray-based assays for the retrospective, large scale evaluation of the inflammatory gene expression profile in archived (typically paraffin-embedded) human pre-malignant and malignant tissue specimens, which could lead to the identification of novel disease biomarkers. The development of pre-clinical models which faithfully mimic disease progression in humans and could stimulate novel diagnostic and therapeutic strategies represents an additional major challenge in the field.
INFLA-CARE collectively possesses the technological capability and proven expertise in disease modelling and tissue analysis to overcome these obstacles and accelerate the translation of knowledge obtained by basic research into novel therapies. Our translational efforts were channelled towards the normalisation of the inflammatory network in cancer-prone tissue prior to the appearance of advanced malignant disease. Combination therapies targeting both the inflammatory microenvironment and the tumor cells have also been evaluated, including conventional cancer therapeutics used in the oncological armamentarium. These strategies will be used in a manner that takes into consideration the molecular information about inflammatory components and signal transduction pathways operating in a tumor type-specific manner.
To address the role of chronic inflammation in cancer, INFLA-CARE pursued the following objectives:
1. To characterize the inflammatory cell components and soluble mediators in inflammation-associated carcinogenesis and to define the early molecular events that trigger tumor initiation in chronically inflammed sites.
2. To define molecular mechanisms and signalling pathways by which inflammation and immunity affect cancer development and progression, with emphasis on NF-kB and MAPK modules, and of the post-transcriptional intracellular network in dictating the nature of the inflammatory microenvironment.
3. To develop novel diagnostic and therapeutic anti-cancer strategies based on the improved understanding of the inflammation-cancer link.
4. Aided by ‘systems biology’ and ‘text mining’ platforms, to integrate research results into meaningful disease profiles which is likely to lead to new scientific and translational hypotheses.
Project Results:
A description of the main S & T results is provided in the attached document.
Potential Impact:
A description of the potential impact of the project is provided in the attached document.
List of Websites:
http://inflacare.imbb.forth.gr/
Epidemiological and experimental evidence supports a link between chronic inflammation and cancer and indicates a role for inflammatory cells in the initiation, progression and metastasis of malignancy. The collaborative integrated project INFLA-CARE has established a European network of scientific and technological excellence in the field of ‘Inflammation & Cancer’ which capitalises on the available expertise with a view to develop effective anti-inflammatory strategies and novel agents or screening platforms for cancer prevention and treatment.
The project has specifically sought to identify molecular and cellular targets for cancer therapy through the development and systematic study of state-of-the-art pre-clinical models of inflammation-driven cancer. During the period of the grant, INFLA-CARE researchers have developed and utilised a variety of in vitro and in vivo models to study the role of cytokines and pro-inflammatory signalling mediators in lung, liver and colorectal carcinogenesis and analyse the molecular pathways involved, including the NF-B and MAPK cascades. The consortium has also discovered novel links between ageing, obesity and inflammation which may impact on carcinogenesis.
By mobilising the outstanding research experience and technological capacities of the network participants, the program has identified and tested new diagnostic and therapeutic strategies which are expected to lead to improved detection, prevention and management of several types of human cancer. It has also discovered novel interactions between the immune system and the response to chemotherapy which will enrich the oncological armamentarium towards ‘patient-tailored’ therapies. These studies have overall yielded significant results which provided the basis for the rational design of novel therapeutic strategies. Procedures and platforms have also been established for the analysis and further evaluation of data that have been generated, including bio-computing software for data integration and concept discovery.
In addition to its major scientific contributions, INFLA-CARE has worked to ensure spreading of scientific excellence and dissemination of knowledge beyond the network, by encouraging innovation and transfer of knowledge and by raising public understanding of scientific and health issues.
Project Context and Objectives:
Dunn and colleagues proposed in 2004 that the relationship between the immune response and tumorigenesis is characterized by 3 stages, collectively called immunoediting. The first stage, termed elimination, represents the period in which the immune system, through successful immunosurveillance, destroys precancerous and cancerous cells. In equilibrium, the second stage, cancer cells have begun to develop capabilities to overcome immunosurveillance but the balance between “immune patrol” and tumorigenesis is still preserved. In the third stage, named escape, the cancer cells manage to override the immune response, resulting in aberrant cell proliferation and tumor development.
The significance of immunoediting in carcinogenesis is highlighted by a seminal paper published in Science by a team of scientists which includes INFLA-CARE researchers, showing that chromosomal content in a tumor is controlled indirectly by an immunosurveillance mechanism which ensures the elimination of hyperploid cells. In particular, this work demonstrated that hyperploid cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin. CRT facilitates the phagocytosis of stressed and dying cells by macrophages as well as by antigen-presenting dendritic cells and it thus part of a barrier mechanism to restrain tumor growth.
On the other hand, the powerful impact of immune cells on cancer has been recognised for many years. Epidemiological studies indicate that approximately 15% of all malignancies can be attributed to infectious agents, such as viruses and bacteria that are able to evade clearance by the immune system and establish a state of chronic inflammatory imbalance. Chronic inflammation has, however, a much broader role in the pathogenesis of cancer. Indeed, experimental and clinical evidence suggests that sustained (and frequently sub-clinical) inflammation triggered by chronic exposure to toxic agents, irritants, oncogenes or autoimmune reactions may contribute to the initiation, progression and metastasis of diverse types of human cancer, including lung, colon and breast.
Inflammatory bowel disease is probably the best-known chronic inflammatory disorder which pre-disposes to cancer and includes Crohn’s disease and ulcerative colitis. Tumorigenesis in colitis-associated cancer (CAC) is thought to evolve via heterotypic interactions between cancer cells, bacteria flora and multiple recruited or resident stromal cell types forming the tumor microenvironment. A stromal component of particular importance to tumorigenesis, especially in CAC, has been the inflammatory component, which appears to promote the neoplastic potential of intestinal epithelial cells (IECs) via the production of proinflammatory cytokines and chemokines, proangiogenic and growth factors, ROS, and proinvasive matrix-degrading proteases. However, the specific signaling pathways underlying inflammatory cell recruitment and their effector functions during tumorigenesis are not fully understood and relatively little is known about the molecular mechanisms mediating resident stromal cell activation and crosstalk with the adjacent tumor epithelium and its microenvironment.
Hepatocellular carcinoma (HCC) is another disease largely attributed to chronic inflammation. HCC is rapidly increasing globally and is now the 4th major cancer killer in men. Present treatments are limited and prognosis upon diagnosis is bleak unless the patient is suitable for an available liver transplantation. There is growing evidence for a disease axis involving interplay between inflammatory, fibrogenic and tumourogenic processes in the diseased liver. The links between liver inflammation and fibrosis are well established and at least 90% of cases of hepatocellular carcinoma develop on the background of severe fibrosis. However, mechanisms are less well established although there is growing evidence that the main fibrogenic cell of the liver, the hepatic stellate cell-derived myofibroblast, contributes to tumour growth by generating a microenvironment that is favourable to tumour growth and survival. In particular the hepatic myofibroblast contributes stable collagen-rich extracellular matrix and a soup of pro-inflammatory molecules that act as growth factors for tumour cells.
Lung cancer is the most common cause of cancer-related deaths in the western world. The recent EUROCARE 3 study has showed that more than 230,000 people in the EU died of lung cancer in 2000, that is one in five of all deaths from cancer. A major risk factor for this type of malignancy is the excessive exposure to chemical carcinogens and particles in tobacco smoke which cause genomic instability and low level, often subclinical, chronic inflammation. There is also an established link between chronic inflammation caused by silica (silicosis) or bacterial infections and lung carcinoma6.
Current treatments for cancer include primary tumour resection and/or aggressive radiotherapy and chemotherapy to achieve both local control and therapy for distant metastases. Conventional cancer treatments are therefore designed to target malignant cells. Tumors, however, frequently develop resistance to therapy as a consequence of the multiple genetic and epigenetic changes they accumulate. Drug resistance represents a major clinical problem and cause of mortality among cancer patients and largely accounts for the limited success of the conventional anti-cancer strategies. Targeting the inflammatory, non-transformed component of tumors may therefore offer an attractive alternative for both the prevention and treatment of malignant disease.
This alternative concept for combating cancer represents the core of the research and technological activities of the collaborative integrated project INFLA-CARE. Through the mobilisation of the research expertise and technological capacities of the INFLA-CARE network participants, we have sought to translate the knowledge of the molecular pathways regulating inflammation-driven cancer into new diagnostic and therapeutic strategies which will be used for the detection, prevention and improved management of several types of human cancer.
The development of such novel approaches to fight cancer has been so far impeded by the near absence of concerted trans-disciplinary collaborative efforts which could rigorously define the influence of the inflammatory microenvironment on tumor growth and, in particular, identify the early molecular events that trigger tumor initiation in chronic inflammatory sites. Technological limitations have also precluded the use of microarray-based assays for the retrospective, large scale evaluation of the inflammatory gene expression profile in archived (typically paraffin-embedded) human pre-malignant and malignant tissue specimens, which could lead to the identification of novel disease biomarkers. The development of pre-clinical models which faithfully mimic disease progression in humans and could stimulate novel diagnostic and therapeutic strategies represents an additional major challenge in the field.
INFLA-CARE collectively possesses the technological capability and proven expertise in disease modelling and tissue analysis to overcome these obstacles and accelerate the translation of knowledge obtained by basic research into novel therapies. Our translational efforts were channelled towards the normalisation of the inflammatory network in cancer-prone tissue prior to the appearance of advanced malignant disease. Combination therapies targeting both the inflammatory microenvironment and the tumor cells have also been evaluated, including conventional cancer therapeutics used in the oncological armamentarium. These strategies will be used in a manner that takes into consideration the molecular information about inflammatory components and signal transduction pathways operating in a tumor type-specific manner.
To address the role of chronic inflammation in cancer, INFLA-CARE pursued the following objectives:
1. To characterize the inflammatory cell components and soluble mediators in inflammation-associated carcinogenesis and to define the early molecular events that trigger tumor initiation in chronically inflammed sites.
2. To define molecular mechanisms and signalling pathways by which inflammation and immunity affect cancer development and progression, with emphasis on NF-kB and MAPK modules, and of the post-transcriptional intracellular network in dictating the nature of the inflammatory microenvironment.
3. To develop novel diagnostic and therapeutic anti-cancer strategies based on the improved understanding of the inflammation-cancer link.
4. Aided by ‘systems biology’ and ‘text mining’ platforms, to integrate research results into meaningful disease profiles which is likely to lead to new scientific and translational hypotheses.
Project Results:
A description of the main S & T results is provided in the attached document.
Potential Impact:
A description of the potential impact of the project is provided in the attached document.
List of Websites:
http://inflacare.imbb.forth.gr/
