วัตถุประสงค์ สามารถอธิบายขั้นตอนการสร้างหลอดเลือดพร้อมทั้งบอก บทบาทของโปรตีนที่เกี่ยวข้องได้ สามารถอธิบายขั้นตอนการสร้างหลอดเลือดพร้อมทั้งบอก บทบาทของโปรตีนที่เกี่ยวข้องได้ สามารถอธิบายการแพร่กระจายของมะเร็ง พร้อมทั้งบอกบทบาท ของโปรตีนที่เกี่ยวข้องได้ สามารถอธิบายการแพร่กระจายของมะเร็ง พร้อมทั้งบอกบทบาท ของโปรตีนที่เกี่ยวข้องได้ 10. การสร้างหลอดเลือดและการแพร่กระจายของมะเร็ง (Angiogenesis and Metastasis) เนื้อหา 10.1 Tumor Angiogenesis 10.2 Invasion and Metastasis

10. Angiogenesis and Metastasis  To survive and grow, all body tissues require a continual supply of oxygen and nutrients accompanied by the removal of carbon dioxide and other waste products Tumor Angiogenesis 1)Arteries carry blood from the heart to the rest of the body. 2)Veins carry blood from the body back toward the heart. 3)Capillaries connect the smallest arteries and veins. The wall of a capillary is only a single cell layer thick. ---> Blood vessels  Like the cells of any other tissue, tumor cells require a network of blood vessels to perform the same tasks.  The vessels that feed and sustain tumors are produced by angiogenesis (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  Vasculogenesis occurs mainly during embryonic development, in which undifferentiated cells are converted into endothelial cells that organize themselves into a network of channels representing the major blood vessels.  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.  Angiogenesis continues to occur after birth when additional blood vessels are required. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

Angiogenesis is required for tumors to grow beyond a few millimeters in diameter  Angiogenesis needs to be precisely regulated in such special situations, turning on for a short time and then stopping.  In adults, the need for new vessels is limited to a few special situations. - normal menstrual cycle - wound healing & tissue repair  When a need for blood vessels arises, angiogenesis activators increase in concentration and inhibitors decrease, triggering the proliferation of endothelial cells and the formation of new vessels.  Judah Folkman (1971) suggested that tumors release signaling molecules that trigger the growth of new blood vessels in the surrounding host tissues and that these new vessels are required to sustain tumor growth.  Once the tiny tumors had failed to link up to the blood vessels, the tumors stopped growing when they reached a diameter of 1-2 mm.

Two experiments showing that tumor growth depends on angiogenesis. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

 It appeared that tumors must trigger development of a blood supply before they can grow beyond a tiny mass.  The process by which cancer cells stimulate the development of a blood supply is called tumor angiogenesis. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

Angiogenesis is controlled by the balance between angiogenesis activators and inhibitors  Cancer cells produce molecules that diffuse through the tiny pores in the filter and activate angiogenesis in the surrounding host tissue.  More than a dozen proteins, as well as smaller molecules, can activate angiogenesis. Some natural stimulators of angiogenesis Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

 Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) appear to be especially important for sustaining tumor growth.  VEGF and FGF produced by many kinds of cancer cells (and certain types of normal cells) trigger angiogenesis by binding to specific receptor proteins located on the surface of endothelial cells. 1) Stimulation of endothelial cell proliferation. 2) Stimulation of endothelial cell migration. 3) Secretion of MMPs (Metrix metalloproteinases) that degrade components of the extracellular matrix Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

 For angiogenesis to proceed the angiogenesis stimulators must overcome the effects of angiogenesis inhibitors that normally restrain the growth of blood vessels.  More than a dozen naturally occurring inhibitors of angiogenesis have been identified, including angiostatin, endostatin, and thrombospondin. Some natural inhibitors of angiogenesis  The balance between the concentration of the inhibitors and the concentration of activators determines whether a tumor will induce the growth of new blood vessels. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

Inhibitors of angiogenesis can restrain tumor growth and spread Angiogenesis- deficient mutant mouse Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

10.2 Invasion and Metastasis  Once angiogenesis has occurred at the site of a primary tumor, the stage is set for tumor cells to invade neighboring tissues and spread to distant sites.  A few kinds of cancers, such as nonmelanoma skin cancers, rarely invade and metastasize.  About half of people with other forms of cancers have tumors that have already begun to spread beyond the site of origin by the time the cancer is diagnosed.  A better understanding the mechanisms that allow cancer cells to spread might be possible to develop improved treatments for cancers Spreading of cancer cells by invasion and metastasis is a complex, multi-step process  Cancers spread through the body via two distinct mechanisms: invasion and metastasis. 1) Invasion refers to the direct migration and penetration of cancer cells into neighboring tissues. 2) Metastasis involves the ability of cancer cells to enter the bloodstream (or other body fluids) and travel to distant sites.

 The events following angiogenesis….. 1) Cancer cells invade surrounding tissues and penetrate through the wall of lymphatic and blood vessels, thereby gaining access to the bloodstream. 2) Cancer cells are then transported by the circulatory system throughout the body. 3) Cancer cells leave the bloodstream and enter particular organs, where they establish new metastatic tumors. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

Changes in cell adhesion, motility, and protease production allow cancer cells to invade surrounding tissues and vessels  Several mechanisms make invasive behavior of cancer cells possible. 1) Cell-cell adhesion proteins are often missing or deficient, allowing cancer cells to separate from the main tumor mass more readily. 2) Activation of cell motility after the loss of cell-cell adhesion. ----> E-cadherin (normally binds epithelial cells to one another) ----> stimulated by signaling molecules (e.g. chemoattractants) 3) Production of protease to degrade the protein barriers that prevent cancer movement. ----> plasminogen activator (produced by most cancer cells)

Active proteases Relatively few cancer cells survive the voyage through the bloodstream  Regional lymph nodes are a common site for the initial spread of cancer.  Cancer cells that initially enter into the lymphatic system eventually arrive in the bloodstream and circulate throughout the body.  The bloodstream is an inhospitable place for most cancer cells and only a tiny number survive the trip to potential sites of metastasis. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

The ability to metastasize differs among cancer cells and tumors  The cells (heterogeneous population) in a primary tumor differ in their ability to metastasize.  The likelihood that metastasis will occur appears to be genetically programmed into the cells of the primary tumor. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

Blood-flow patterns often dictate where cancer cells will metastasize  The pattern of blood-flow in the circulatory system determines where cancer cells are likely to become lodged.  Stomach and colon cancers frequently metastasize to the liver.  Prostate and breast cancers often metastasize to bone.  Many forms of cancer tend to metastasize to the lungs.  Lung cancer metastasize to many different organs. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

Organ-specific factors play a role in determining where cancer cells will metastasize  Paget’s idea (Stephen Paget,1889) is often referred to as the “seed and soil” hypothesis.  Metastasis only takes place where the seed ( a cancer cell) and the soil (a particular organ) are compatible.  The ability to grow in different locations is affected by interactions between cancer cells and molecules present in the organs to which they are delivered.  Bone cells produce growth factors that stimulate the proliferation of prostate cancer cells Some of the cellular properties involved in invasion and metastasis arise during tumor progression  Cancer is a disease whose properties change with time.  Individual cancer cells often acquire gene mutations and alter the genes they express, turning on some genes and turning off others.  Such alterations create a population of cells whose properties, including the ability to invade and metastasize, gradually change over time.

The immune system can inhibit the process of metastasis  Cancer cells are not literally of “foreign” origin, but they often exhibit molecular changes that allow the immune system to recognize the cells as being abnormal.  Animal experiments suggest that in some cases, attack by the immune system does limit the process of metastasis. Lung cancer cells H-2K = cell surface MHC molecule Recognized by cytotoxic T lymphocytes Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

Invasion and Metastasis involve a variety of Tumor-Host interactions  The behavior of the malignant tumors depends not just on the traits of cancer cells, but also on interactions between cancer cells and normal cells of the host. Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco

Specific genes promote or suppress the ability of cancer cells to metastasize 1) Metastasis promoting genes: code for proteins that stimulate events associated with invasion and metastasis 2) Metastasis suppressor genes: code for proteins that inhibit events associated with invasion and metastasis ----> MMP genes ----> Twist gene :- contributes to the lost of adhesive properties ----> CAD1 gene:- codes for E-cadherin ----> NM23 gene ----> KiSS1 gene ----> KAI1 gene ----> BRMS1 gene ----> MKK4 gene Some of these genes code for proteins involved in cell adhesion and motility.