Lecture 3 - BS3540
The Extracellular Matrix (ECM)
Components:
Fibrous glycoproteins include:
Collagen: The most abundant protein in the human body, providing structural support and strength to tissues.
Fibrin: Important for blood clotting and tissue repair, forming a fibrous network that supports cell spreading.
Elastin: Provides elasticity, allowing tissues to resume their shape after stretching or contracting.
Large glycoproteins:
Fibronectin: Acts as a bridge between cells and the ECM, influencing cell adhesion and migration.
Laminin: Critical for the structure of the basement membrane, influencing cell differentiation and the adhesion of epithelial and other cells.
Large proteoglycans: e.g., perlecan, which has important roles in cell signaling and providing structural integrity in tissues.
Proteoglycans are polypeptides that carry glycosaminoglycans, which are long unbranched and highly negatively charged polysaccharide chains.
Cell Interactions with ECM: Cells interact with the ECM via cell surface proteoglycans and adhesion proteins like integrins, forming focal adhesions that are crucial for cell signaling and communication with the environment.
Basement Membranes: Some cells reside on the prominent ECM layers known as basement membranes, which are essential in providing structural support and compartmentalization between different tissue types.
Angiogenesis and Metastasis
Transformation: The process by which normal cells undergo genetic changes to acquire properties of cancer cells, leading to uncontrolled growth.
Induction of Angiogenesis: Cancer cells stimulate the formation of new blood vessels from existing ones to supply nutrients and oxygen to the growing tumor.
Motility and Invasion: Invasive cancer cells can detach from the primary tumor and migrate to other tissues, aided by the degradation of the ECM components.
Adherence: Cancer cells must adhere to the new ECM in the target tissue to establish secondary tumors, often facilitated by adhesion molecules.
Arrest in Capillary Beds: Cancer cells can get trapped in the small blood vessels of distant organs, preparing for extravasation.
Embolism and Circulation: Cancer cells travel through the bloodstream to disseminate and form new metastatic sites.
Growth Extravasation into Organ Parenchyma: Upon exiting the bloodstream, cancer cells invade the parenchyma of organs, establishing secondary tumors.
Specific Response to the Organ Microenvironment: Metastatic cells adapt to the unique microenvironment of the target organ, a process influenced by local signaling molecules and ECM composition.
Tumor Cell Proliferation and Induction of Organ-Specific Angiogenesis: Metastatic tumors often induce angiogenesis specific to the organ they invade, facilitating further growth and survival.
Metastases: The spread of cancer from one organ to another, representing a major challenge in cancer therapy.
Fibronectin
Structure: A glycoprotein with a molecular weight of , existing as a homodimer formed by two identical polypeptides, with several splice variants contributing to its functional diversity.
Multiple Domains: These domains facilitate various interactions necessary for cell attachment, migration, and differentiation, relevant in wound healing and embryonic development.
RGD Motif: The Arg-Gly-Asp (RGD) motif within fibronectin is a critical binding site for integrins on the cell surface, playing a pivotal role in cell adhesion.
Cell Adhesive Recognition Sequences include:
55: Suggestive of a second site that enhances fibronectin’s function.
RGD: Important for promoting integrin binding and cell attachment.
H: Potential sites in the heparin-binding domain for interaction with heparan sulfate.
CS1: The CS1 site in the alternatively spliced IIICS region, contributing to the specific interaction of certain cell types.
REDV: The Arg-Glu-Asp-Val site, involved in endothelial and epithelial cell interactions.
Laminin
Structure: Composed of three chains (A, B1, B2), it exhibits a molecular weight of approximately . Its structural model illustrates various functional domains, each designated by Roman numerals, and features a terminal domain designated as G that is critical for interaction with other ECM components.
Heparin-Binding Domains: The model includes regions known as Hep-1, Hep-2, and Hep-3, located strategically on the molecule, facilitating interactions with various growth factors and cell surface receptors.
Structure of Glycosaminoglycans
Included Types: Glycosaminoglycans (GAGs) play essential roles in hydration, cell signaling, and molecular transport, with types including Hyaluronate, Chondroitin sulfates, Dermatan sulfate, Heparan sulfate, Heparin, and Keratan sulfate.
Chemical Composition: GAGs are made up of repeating disaccharide units, where GlcUA (glucuronic acid) and IdUA (iduronic acid), along with GlcN (N-acetylglucosamine) and GalN (N-acetylgalactosamine), contribute to their unique biochemical properties and functions in the ECM.