Mechanisms of cell invasion and fibrovascular complications in cancer and diabetic retinopathy

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Invasion of the extracellular matrix (ECM) and dissemination via the lymphatic and blood circulation are key events in tumour progression. These events involve biological processes where responses to growth stimuli, cytoskeletal and ECM remodelling are interconnected. Plasticity of cell invasion is used as a way to cope with the tumour microenvironment that is continuously changing as a result of tumour progression. In addition, the accumulating mutation load in progressing tumours provides cell inherent triggers that tweak cell behaviour, including invasion. Thus, cancer cell plasticity and adaptability to environmental challenges confound therapeutic efforts aimed at eradicating metastases and halting tumour spread. Cell invasion is also harnessed by the cellular tumour microenvironment, including cancer-associated fibroblasts (CAFs), endothelial cells (ECs) and macrophages. Lymphatic and blood ECs also utilize the invasion machinery during developmental and physiological angiogenesis as well as in pathological vascular remodelling, like tumour angiogenesis and microvascular complications of diabetes. Understanding the context-dependent mechanisms of cell invasion and plasticity can provide new targets for improved therapies. Invading cancer cells as well as ECs upregulate and use membrane type matrix metalloproteinases (MT-MMPs) for invasion into the ECM. By cooperating with protein kinase signalling and by cleaving cell-surface proteins, MT-MMPs further modify cell behaviour. The purpose of this thesis was to study the tissue microenvironment-dependent molecular networks involved in tumour invasion and pathological vascular remodelling. We found a cooperative signalling mechanism between MT1-MMP and the receptor tyrosine kinase EphA2, whereby MT1-MMP‒dependent cleavage of EphA2 provides breast cancer cells with a mechanism for switching from collective to single-cell invasion. Studies on the MT1-MMP cytosolic tail revealed a new regulatory mechanism for mesenchymal invasion by linking MT1-MMP to the actin-cytoskeleton, through Src-regulated interaction with the cytoskeletal protein palladin. In melanoma, MT3-MMP dependent cleavages of MT1-MMP and of cell surface L1 cell adhesion molecule limited their activities towards pericellular collagen degradation and cell junction disassembly, and blood endothelial transmigration, respectively. These mechanisms supported nodular-type growth and lymphatic vessel invasion of adhesive collagen-surrounded melanoma cell collectives. Pathological angiogenesis also involves the invasion of the ECM as well as interactions with the immediate and soluble microenvironment for efficient neovessel formation. During the work for this thesis we developed an ex vivo culture model for the study of pathological vascular remodelling in the context of relevant interactions between the cellular and acellular tissue microenvironment, by utilizing proliferative diabetic retinopathy patient-derived neovascular tufts and corresponding vitreous fluid. We described that the lymphatic endothelial involvement, also discovered during the work for this thesis, is supported by the ischemia- and inflammation-induced vitreal microenvironment, thus bringing a new concept to the PDR mechanisms and targeting options. The findings of this thesis help us to better understand the molecular mechanisms behind the microenvironment-dependent endothelial and cancer cell behaviour plasticity that critically contributes to disease progression and drug responses in debilitating diseases like cancer and diabetes.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-3945-0
Electronic ISBNs978-951-51-3946-7
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3111 Biomedicine

Cite this

@phdthesis{cbd4da1ff6e344e7bd345f3d3eb25eaf,
title = "Mechanisms of cell invasion and fibrovascular complications in cancer and diabetic retinopathy",
abstract = "Invasion of the extracellular matrix (ECM) and dissemination via the lymphatic and blood circulation are key events in tumour progression. These events involve biological processes where responses to growth stimuli, cytoskeletal and ECM remodelling are interconnected. Plasticity of cell invasion is used as a way to cope with the tumour microenvironment that is continuously changing as a result of tumour progression. In addition, the accumulating mutation load in progressing tumours provides cell inherent triggers that tweak cell behaviour, including invasion. Thus, cancer cell plasticity and adaptability to environmental challenges confound therapeutic efforts aimed at eradicating metastases and halting tumour spread. Cell invasion is also harnessed by the cellular tumour microenvironment, including cancer-associated fibroblasts (CAFs), endothelial cells (ECs) and macrophages. Lymphatic and blood ECs also utilize the invasion machinery during developmental and physiological angiogenesis as well as in pathological vascular remodelling, like tumour angiogenesis and microvascular complications of diabetes. Understanding the context-dependent mechanisms of cell invasion and plasticity can provide new targets for improved therapies. Invading cancer cells as well as ECs upregulate and use membrane type matrix metalloproteinases (MT-MMPs) for invasion into the ECM. By cooperating with protein kinase signalling and by cleaving cell-surface proteins, MT-MMPs further modify cell behaviour. The purpose of this thesis was to study the tissue microenvironment-dependent molecular networks involved in tumour invasion and pathological vascular remodelling. We found a cooperative signalling mechanism between MT1-MMP and the receptor tyrosine kinase EphA2, whereby MT1-MMP‒dependent cleavage of EphA2 provides breast cancer cells with a mechanism for switching from collective to single-cell invasion. Studies on the MT1-MMP cytosolic tail revealed a new regulatory mechanism for mesenchymal invasion by linking MT1-MMP to the actin-cytoskeleton, through Src-regulated interaction with the cytoskeletal protein palladin. In melanoma, MT3-MMP dependent cleavages of MT1-MMP and of cell surface L1 cell adhesion molecule limited their activities towards pericellular collagen degradation and cell junction disassembly, and blood endothelial transmigration, respectively. These mechanisms supported nodular-type growth and lymphatic vessel invasion of adhesive collagen-surrounded melanoma cell collectives. Pathological angiogenesis also involves the invasion of the ECM as well as interactions with the immediate and soluble microenvironment for efficient neovessel formation. During the work for this thesis we developed an ex vivo culture model for the study of pathological vascular remodelling in the context of relevant interactions between the cellular and acellular tissue microenvironment, by utilizing proliferative diabetic retinopathy patient-derived neovascular tufts and corresponding vitreous fluid. We described that the lymphatic endothelial involvement, also discovered during the work for this thesis, is supported by the ischemia- and inflammation-induced vitreal microenvironment, thus bringing a new concept to the PDR mechanisms and targeting options. The findings of this thesis help us to better understand the molecular mechanisms behind the microenvironment-dependent endothelial and cancer cell behaviour plasticity that critically contributes to disease progression and drug responses in debilitating diseases like cancer and diabetes.",
keywords = "Biomarkers, Breast Neoplasms, +pathology, Carcinoma, Cell Differentiation, Cell Line, Tumor, Collagen, +metabolism, Cytoskeletal Proteins, Diabetic Retinopathy, Endothelial Progenitor Cells, Endothelium, Lymphatic, Extracellular Matrix, Gene Expression, Matrix Metalloproteinases, Melanoma, +enzymology, Neoplasm Invasiveness, Neoplasm Transplantation, Phosphoproteins, Protein Transport, Proteolysis, Retinal Neovascularization, RNA, Small Interfering, Receptor, EphA2, Time-Lapse Imaging, Tissue Array Analysis, rhoA GTP-Binding Protein, 3111 Biomedicine",
author = "Erika Gucciardo",
note = "M1 - 86 s. + liitteet",
year = "2018",
language = "English",
isbn = "978-951-51-3945-0",
series = "Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis",
publisher = "University of Helsinki",
number = "4/2018",
address = "Finland",

}

Mechanisms of cell invasion and fibrovascular complications in cancer and diabetic retinopathy. / Gucciardo, Erika.

Helsinki : University of Helsinki, 2018. 86 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Mechanisms of cell invasion and fibrovascular complications in cancer and diabetic retinopathy

AU - Gucciardo, Erika

N1 - M1 - 86 s. + liitteet

PY - 2018

Y1 - 2018

N2 - Invasion of the extracellular matrix (ECM) and dissemination via the lymphatic and blood circulation are key events in tumour progression. These events involve biological processes where responses to growth stimuli, cytoskeletal and ECM remodelling are interconnected. Plasticity of cell invasion is used as a way to cope with the tumour microenvironment that is continuously changing as a result of tumour progression. In addition, the accumulating mutation load in progressing tumours provides cell inherent triggers that tweak cell behaviour, including invasion. Thus, cancer cell plasticity and adaptability to environmental challenges confound therapeutic efforts aimed at eradicating metastases and halting tumour spread. Cell invasion is also harnessed by the cellular tumour microenvironment, including cancer-associated fibroblasts (CAFs), endothelial cells (ECs) and macrophages. Lymphatic and blood ECs also utilize the invasion machinery during developmental and physiological angiogenesis as well as in pathological vascular remodelling, like tumour angiogenesis and microvascular complications of diabetes. Understanding the context-dependent mechanisms of cell invasion and plasticity can provide new targets for improved therapies. Invading cancer cells as well as ECs upregulate and use membrane type matrix metalloproteinases (MT-MMPs) for invasion into the ECM. By cooperating with protein kinase signalling and by cleaving cell-surface proteins, MT-MMPs further modify cell behaviour. The purpose of this thesis was to study the tissue microenvironment-dependent molecular networks involved in tumour invasion and pathological vascular remodelling. We found a cooperative signalling mechanism between MT1-MMP and the receptor tyrosine kinase EphA2, whereby MT1-MMP‒dependent cleavage of EphA2 provides breast cancer cells with a mechanism for switching from collective to single-cell invasion. Studies on the MT1-MMP cytosolic tail revealed a new regulatory mechanism for mesenchymal invasion by linking MT1-MMP to the actin-cytoskeleton, through Src-regulated interaction with the cytoskeletal protein palladin. In melanoma, MT3-MMP dependent cleavages of MT1-MMP and of cell surface L1 cell adhesion molecule limited their activities towards pericellular collagen degradation and cell junction disassembly, and blood endothelial transmigration, respectively. These mechanisms supported nodular-type growth and lymphatic vessel invasion of adhesive collagen-surrounded melanoma cell collectives. Pathological angiogenesis also involves the invasion of the ECM as well as interactions with the immediate and soluble microenvironment for efficient neovessel formation. During the work for this thesis we developed an ex vivo culture model for the study of pathological vascular remodelling in the context of relevant interactions between the cellular and acellular tissue microenvironment, by utilizing proliferative diabetic retinopathy patient-derived neovascular tufts and corresponding vitreous fluid. We described that the lymphatic endothelial involvement, also discovered during the work for this thesis, is supported by the ischemia- and inflammation-induced vitreal microenvironment, thus bringing a new concept to the PDR mechanisms and targeting options. The findings of this thesis help us to better understand the molecular mechanisms behind the microenvironment-dependent endothelial and cancer cell behaviour plasticity that critically contributes to disease progression and drug responses in debilitating diseases like cancer and diabetes.

AB - Invasion of the extracellular matrix (ECM) and dissemination via the lymphatic and blood circulation are key events in tumour progression. These events involve biological processes where responses to growth stimuli, cytoskeletal and ECM remodelling are interconnected. Plasticity of cell invasion is used as a way to cope with the tumour microenvironment that is continuously changing as a result of tumour progression. In addition, the accumulating mutation load in progressing tumours provides cell inherent triggers that tweak cell behaviour, including invasion. Thus, cancer cell plasticity and adaptability to environmental challenges confound therapeutic efforts aimed at eradicating metastases and halting tumour spread. Cell invasion is also harnessed by the cellular tumour microenvironment, including cancer-associated fibroblasts (CAFs), endothelial cells (ECs) and macrophages. Lymphatic and blood ECs also utilize the invasion machinery during developmental and physiological angiogenesis as well as in pathological vascular remodelling, like tumour angiogenesis and microvascular complications of diabetes. Understanding the context-dependent mechanisms of cell invasion and plasticity can provide new targets for improved therapies. Invading cancer cells as well as ECs upregulate and use membrane type matrix metalloproteinases (MT-MMPs) for invasion into the ECM. By cooperating with protein kinase signalling and by cleaving cell-surface proteins, MT-MMPs further modify cell behaviour. The purpose of this thesis was to study the tissue microenvironment-dependent molecular networks involved in tumour invasion and pathological vascular remodelling. We found a cooperative signalling mechanism between MT1-MMP and the receptor tyrosine kinase EphA2, whereby MT1-MMP‒dependent cleavage of EphA2 provides breast cancer cells with a mechanism for switching from collective to single-cell invasion. Studies on the MT1-MMP cytosolic tail revealed a new regulatory mechanism for mesenchymal invasion by linking MT1-MMP to the actin-cytoskeleton, through Src-regulated interaction with the cytoskeletal protein palladin. In melanoma, MT3-MMP dependent cleavages of MT1-MMP and of cell surface L1 cell adhesion molecule limited their activities towards pericellular collagen degradation and cell junction disassembly, and blood endothelial transmigration, respectively. These mechanisms supported nodular-type growth and lymphatic vessel invasion of adhesive collagen-surrounded melanoma cell collectives. Pathological angiogenesis also involves the invasion of the ECM as well as interactions with the immediate and soluble microenvironment for efficient neovessel formation. During the work for this thesis we developed an ex vivo culture model for the study of pathological vascular remodelling in the context of relevant interactions between the cellular and acellular tissue microenvironment, by utilizing proliferative diabetic retinopathy patient-derived neovascular tufts and corresponding vitreous fluid. We described that the lymphatic endothelial involvement, also discovered during the work for this thesis, is supported by the ischemia- and inflammation-induced vitreal microenvironment, thus bringing a new concept to the PDR mechanisms and targeting options. The findings of this thesis help us to better understand the molecular mechanisms behind the microenvironment-dependent endothelial and cancer cell behaviour plasticity that critically contributes to disease progression and drug responses in debilitating diseases like cancer and diabetes.

KW - Biomarkers

KW - Breast Neoplasms

KW - +pathology

KW - Carcinoma

KW - Cell Differentiation

KW - Cell Line, Tumor

KW - Collagen

KW - +metabolism

KW - Cytoskeletal Proteins

KW - Diabetic Retinopathy

KW - Endothelial Progenitor Cells

KW - Endothelium, Lymphatic

KW - Extracellular Matrix

KW - Gene Expression

KW - Matrix Metalloproteinases

KW - Melanoma

KW - +enzymology

KW - Neoplasm Invasiveness

KW - Neoplasm Transplantation

KW - Phosphoproteins

KW - Protein Transport

KW - Proteolysis

KW - Retinal Neovascularization

KW - RNA, Small Interfering

KW - Receptor, EphA2

KW - Time-Lapse Imaging

KW - Tissue Array Analysis

KW - rhoA GTP-Binding Protein

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-3945-0

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - University of Helsinki

CY - Helsinki

ER -

Gucciardo E. Mechanisms of cell invasion and fibrovascular complications in cancer and diabetic retinopathy. Helsinki: University of Helsinki, 2018. 86 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 4/2018).