Cancer Biology: How Cancers Spread (2024/2025) - PDF

CANCER BIOLOGY HOW CANCERS SPREAD Dr. HAYTHAM MOHAMED First Semester Lecture ACADEMIC YEAR 2024/2025  CANCER TUMOR MOLECULAR CELLS AND IMMUNOLOGY CHANGES IN DNA...

CANCER BIOLOGY HOW CANCERS SPREAD Dr. HAYTHAM MOHAMED First Semester Lecture ACADEMIC YEAR 2024/2025  CANCER TUMOR MOLECULAR CELLS AND IMMUNOLOGY CHANGES IN DNA DAMAGE CANCER CELLS Previously Objectives 1 2 3 TUMOR INVASION AND Tumor-Host ANGIOGENESIS METASTASIS Interactions Why is it Important to Understand Cancer Metastasis? ▪ Because they can arise in almost any vital organ, metastases rather than primary tumors are responsible for most cancer deaths. without metastases tumors cannot grow beyond a few millimeters ▪ Metastasis is responsible for more than 90% of cancer-related deaths. ▪ Like the cells of any other tissue, tumor cells require a network of blood vessels to perform these same tasks (supply of oxygen and nutrients accompanied by the removal of carbon dioxide and other waste products) TUMOR ANGIOGENESIS ANGIOGENESIS ▪ Angiogenesis, a term that refers to the process by which new blood vessels sprout and grow from pre-existing vessels in the surrounding normal tissues. ▪ Angiogenesis is Prominent in Embryos but Relatively Infrequent in Adults and restricted to a few special situations just like wound healing But how Angiogenesis occurs???  Angiogenesis steps ▪ 1- During vasculogenesis, which occurs mainly during embryonic development, undifferentiated cells are converted into endothelial cells that organize themselves into a network of channels representing the major blood vessels. ▪ 2- Angiogenesis refers to the growth and proliferation of the endothelial cells that line the inner surface of existing blood vessels, forming buds that sprout from the vessel wall and develop into new vessels. ▪ 1971, Judah Folkman proposed that tumors release signaling molecules that trigger angiogenesis that is, growth of blood vessels in the surrounding host tissues and that these new vessels are required for tumors to grow beyond a tiny, localized clump of cells 3 experiments to prove that tumors need Angiogenesis Experiment 1 ▪ Cancer cells were injected into Normal thyroid gland removed from a rabbit then then nutrient solution was pumped into the organ ▪ The cancer cells divided for a few days but suddenly stopped when the tumor mass reached a diameter of 1 to 2 millimeters. ▪ When tumor cells were removed from the thyroid gland and injected back into animals, cell proliferation resumed, and massive tumors developed. Judah Folkman experiment Experiment 2 ▪ Cancer cells were either injected into the liquid- filled anterior chamber of a rabbit’s eye, where there are no blood vessels, or were placed directly on the iris which have blood vessels. ▪ Tumor cells in the anterior chamber, nourished solely by diffusion, remain alive but stop growing before the tumor mass reaches 1 millimeter in diameter. ▪ In contrast, blood vessels quickly infiltrate the cancer cells implanted on the iris, allowing the tumors to grow to thousands of times their original mass. Judah Folkman experiment Experiment 3 ▪ Cancer cells were placed inside a chamber surrounded by a filter possessing tiny pores through which cells cannot pass ▪ After injection under animal skin: New capillaries begin to proliferate in the surrounding host tissue. In contrast, normal cells placed in the same type of chamber do not stimulate blood vessel growth. ▪ Cancer cells produce molecules that diffuse through the tiny pores in the filter and activate angiogenesis in the surrounding host tissue. The main angiogenesis-activating molecules ▪ Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are the main angiogenesis-activating molecules. ▪ Cancer cells secrete VEGF molecules that bind to receptor proteins located on the surface of endothelial cells. The binding of VEGF to its receptor leads to the activation of a series of signal transduction proteins that trigger changes in gene expression and cell behavior. ▪ The net result is the stimulation of endothelial cell proliferation and migration as well as the secretion of matrix metalloproteinases (MMPs) that degrade components of the extracellular matrix. ▪ The proliferating endothelial cells are gradually organized into new networks of blood vessels. ▪ Tumor angiogenesis process by which cancer cells stimulate the development of a blood supply. ▪ Angiogenesis Is Controlled by the Balance Between Angiogenesis Activators and Inhibitors - Angiostatin and endostatin are important angiogenesis inhibitors. ▪ Inhibitors of Angiogenesis Can Restrain Tumor Growth and Spread ▪ Inhibitors of Angiogenesis are used as cancer therapy such as AVASTIN ▪ Tomatoes and green tea contain are anti- angiogenic compounds  INVASION AND METASTASIS BASIC DEFINITIONS ▪ Invasion refers to the direct migration and penetration of cancer cells into neighboring tissues ▪ Metastasis involves the ability of cancer cells to enter the bloodstream (or other body fluids) and travel to distant sites, where they form new tumors that are not physically contiguous with the primary tumor. ▪ Tumor dormancy, in which cancer cells spread from a primary tumor to another organ and form tiny clumps of cancer cells that remain dormant for prolonged periods of time. A significant factor contributing to this dormancy is the lack of angiogenesis, Immune Evasion and Adaptation to a Foreign Microenvironment ▪ Micrometastases are small clusters of cancer cells that have detached from the primary tumor and traveled to other organs or tissues, where they form tiny, often clinically undetectable, secondary tumor sites. ▪ These micrometastases can remain in a dormant state for prolonged periods, where they neither grow significantly nor cause symptoms. ▪ Micrometastases can eventually "wake up" from dormancy, leading to aggressive growth. Triggers for reactivation can include Angiogenesis Initiation and Changes in the Microenvironment. METASTASIS STEPS 1- Cancer cells adhere to and invade through the basal lamina, degrade the extracellular matrix of the underlying tissue to open up a path through which the cells can move, and finally adhere to and invade through the basal lamina of a tiny vessel, thereby entering the circulatory system. ➁ The cancer cells are transported via the bloodstream to distant sites. ➂ The cancer cells become arrested in a capillary located in another organ, adhere to and invade through the basal lamina of the capillary wall, enter the surrounding tissue, and start to grow again. Factors that promote invasion and Metastasis 1- loss of cell-cell adhesion proteins. Who is responsible ??? Such as E-cadherin 2- Increased motility of cancer cells, by secretion of molecules that attract migrating cancer cells such as Rho family GTPases 3- Ability of cancer cells to produce proteases that degrade protein-containing structures that would otherwise act as barriers to cancer cell movement. ▪ Restoring E-cadherin to cancer cells lacking this molecule inhibits their ability to form invasive tumors Activation of proteases Cancer cell secret plasminogen activator, an enzyme that converts the inactive precursor plasminogen into the active protease plasmin. The plasmin performs two tasks: (1) It degrades components of the basal lamina and the extracellular matrix, thereby facilitating tumor invasion (2) It cleaves inactive precursors of matrix metalloproteinases, produced mainly by surrounding host cells, into active enzymes that also degrade the basal lamina and extracellular matrix. Voyage Through the Bloodstream ▪ Cancer cells can penetrate the walls of lymphatic vessels, the cells are first carried to regional lymph nodes, where they may become lodged and grow. ▪ Lymph nodes have numerous interconnections with blood vessels, so cancer cells that initially enter into the lymphatic system eventually find their way into the bloodstream. ▪ However, the bloodstream is a relatively inhospitable place for most cancer cells, and fewer than one in a thousand cells survive the trip to a potential site of metastasis. Blood Flow and Organ-Specific Factors Determine Sites of Metastasis ▪ Although the bloodstream carries cancer cells everywhere in the body, the final distribution of metastases is not random, nor is it the same for every type of cancer. ▪ For example, stomach and colon cancers frequently metastasize to the liver. Prostate and breast cancers often metastasize to bone, and many forms of cancer tend to metastasize to the lungs while lung cancers metastasize to many different organs. Stephen Paget ,1889 “seed and soil” hypothesis ▪ Cancer cells are carried to a variety of organs by the bloodstream, but only a few sites provide an optimal environment for the growth of a particular type of cell. ▪ In other words, metastasis only takes place where the seed (a cancer cell) and the soil (a particular organ) are compatible. Specific Genes Promote or Suppress the Ability of Cancer Cells to Metastasize ▪ The positively acting genes, called metastasis promoting genes, code for proteins that stimulate events associated with invasion and metastasis. Such as MMPs and VEGF ▪ The negatively acting genes, called metastasis suppressor genes, code for proteins that inhibit events associated with invasion and metastasis. Such as KAI1 and KISS1 Immune system and metastasis ▪ Immune system can inhibit the process of metastasis ▪ D122 lung cancer cells, which express cell surface H-2D (MHC Molecule molecules, produce many metastases and few T cells. ▪ A9 lung cancer cells, which express both H- 2D and H-2K (MHC molecules), few metastases and many T cells produced. ▪ If the H-2K gene is introduced into D122 cells, the cells lose their ability to metastasize. few metastases and many T cells produced. ▪ H-2K enhances the immune recognition of the tumor cells, allowing for a more effective immune response. TUMOR-HOST INTERACTIONS Cancer can cells harness normal cells Normal cells can fight cancer cells Examples : Examples : ▪ Angiogenesis is triggered by growth factors Normal tissues also contain cells and molecules released by tumor cells that act on normal that are capable of hindering invasion and endothelial cells of the surrounding host tissue, metastasis. thereby stimulating the proliferation of new blood vessels. ▪ For example, immune lymphocytes are ▪ Invasion motility of cancer cells and is facilitated by capable of attacking and destroying cancer both tumor- and host-derived proteases that cells degrade normal extracellular structures such as the basal lamina and the extracellular matrix. Why? ▪ In addition, normal tissues produce protease (plasminogen exist in all tissues) inhibitors that reduce the activity of the ▪ Growth of metastases at distant sites is simulated proteases that cancer cells require for by growth factors and other molecules produced degrading the basal lamina and extracellular by cells residing in the organs being invaded. matrix. Next Lecture What Causes Cancer? END OF LECTURE 4