How cancer spread? (pt.2)

Angiogenesis is required for tumors to grow beyond a few millimeters in diameter

Tumors release signaling molecules that trigger angiogenesis- that is, growth of blood vessels- in the surrounding host tissues, and these new vessels are required for tumors to grow beyond a tiny, localized clump of cells.

Two experiments showing the requirement for angiogenesis.

(a) Cancer cells were injected into an isolated rabbit thyroid gland that was kept alive by pumping a nutrient solution into its main blood vessel. The tumor cells, alive but dormant in the isolated thyroid gland,  fail to link up to the organ's blood vessels, and the tumor stops growing when it reaches a diameter of roughly 1-2 millimeters.

(b) Cancer cells were either injected into the liquid-filled anterior chamber of a rabbit's eye, where there are no blood vessels, or they were placed directly on the iris. Tumor cells in the anterior chamber, nourished solely by diffusion, remain alive but stop growing before the tumor reaches a 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.

Blood vessels growth is controlled by a balance between Angiogenesis activators and inhibitors

When normal cells were placed in the chamber surrounded by a filter , they do not stimulate blood vessels growth. In contrast, 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 are proteins called vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), normal cells as well as cancer cells produce these proteins. When cancer cells release these proteins into the surrounding tissue, they bind to receptor proteins on the surface of the endothelial cells that form the lining of blood vessels. This binding also 

secrete protein-degrading enzymes called metalloproteinases (MMPs). The MMPs break down the ECM, thereby permitting the endothelial cells to migrate into the surrounding tissues. As they migrate, the proliferating endothelial cells become organized into hollow tubes that develop into new blood vessels.

Also, for angiogenesis to proceed, these proteins must overcome the effects of angiogenesis inhibitors ,like angiostatin, endostatin and thrombospondin, that can restrain the growth of blood vessels. A finely tuned balance between the concentration of angiogenesis inhibitors and activators determines whether a tumor will induce the growth of new blood vessels. When tumors trigger angiogenesis, it is usually accomplished by an increase in the production of angiogenesis activators and a simultaneous decrease in the production of angiogenesis inhibitors.

Cancer cells spread by invasion and metastasis.

 The ability of cancer cells to spread is based on two distinct mechanisms:

Invasion refers to the direct migration and penetration of cancer cells into neighboring tissues, whereas, metastasis involves the ability of cancer cells to enter the bloodstream (or other body fluids) and travel to distant sites, where they form tumors- called metastases.

The events following angiogenesis can be grouped into three main steps.

First, cancer cells invade surrounding tissues and penetrate through the walls of lymphatic and blood vessels, thereby gaining access to the bloodstream. Second, the cancer cells are transported by the circulatory system throughout the body. And third, cancer cells leave the bloodstream and enter various organs, where they establish new metastatic tumors. If cells from the initial tumor fail to complete any of these steps, or if any of the steps can be prevented, metastasis will not occur.

Changes in cell adhesion, motility and protease production allow cancer cells to invade surrounding tissues and vessels.

Several mechanisms make the invasion behavior possible. The first involves changes in the cell surface proteins that cause cells to adhere to one another. Such proteins are often missing or defective in cancer cells, which allows cell to separate from the main tumor more readily. One crucial molecule is E-cadherin, a cell-cell adhesion protein whose loss underlies the reduced adhesiveness of many epithelial cancers. Cancer cells lack E-cadherin.

A second factor underlying invasive behavior is the increased motility of cancer cells, which is stimulated by signaling molecules produced by surrounding host tissues or by the cancer cells themselves. Some of these signaling molecules can act as chemoattractant that serve as guiding signals that attract migrating cancer cells. Activation of the Rho family GTPases (Rho, Rac and Cdc42) plays a central role in the stimulation of cell motility that leads to invasion and metastasis.

Another trait is the ability of cancer cells to produce proteases that degrade protein-containing structures that form the backbone of the basal lamina, that would otherwise act as barriers to cancer cell movement.  One such protease is plasminogen activator, an enzyme that converts the inactive precursor plasminogen into the active protease plasmin. The plasmin performs two tasks: (a) It degrades components of the basal lamina and the ECM, thereby facilitating tumor invasion. (b) it cleaves inactive precursors of matrix metalloproteinases into active enzymes. These proteases allow cancer cells to penetrate basal lamina, facilitating its migration until they reach tiny blood or lymphatic vessels.

Relatively few cancer cells survive the voyage through the bloodstream.

The bloodstream is a relatively inhospitable place for most cancer cells and fewer than one in a thousand cells survives the trip to a potential site of metastasis.

 An experiment designed to find out that if these successful cells are simply random tumor cell population or they are especially well suited for metasizing. In this exp., mouse melanoma cells were injected into the tail vein of a mouse. After a small number of metastases arose in the lungs, cells from these lung tumors were removed and injected into another mouse. When this cycle was repeated ten times, the final population of melanoma cells produced many more lung metastases than were produced by the original cells. This means that  Initial melanoma consisted of a heterogenous population of cells with differing properties and that repeated isolation and reinjection of cells derived from successful metastases gradually selected for those cells that were best suited for metastasizing. 

Cell populations that are derived from a single initial cell, are called clones.

Blood flow patterns and organ- specific factors determine the sites of metastasis.

Although the bloodstream carries cancer cells throughout the entire body, metastases develop preferentially at certain sites. One factor responsible for this specificity is related to blood- flow patterns. Based solely on size considerations, circulating cancer cells are most likely to become lodged in capillaries. After becoming stuck there, cancer cells penetrate the walls of these tiny vessels, enter the surrounding tissues, and seed the development of new tumors. As the first capillary bed by the cancer cells will be in the lungs, lungs are the most frequent site of metastasis.

For cancers of the stomach and colon, cancer cells entering the bloodstream are first carried to the liver, where the vessels break up into a bed of capillaries. The interactions between cancer cells and the microenvironment in the organs they are delivered to gives the reason why cancer cells grow best at particular sites. For e.g., prostrate cancer commonly metastasizes to bone. Bone cells produce specific growth factors that stimulate the proliferation of prostrate cancer cells. 

The immune system influences the growth and spread of cancer cells.

Immune system can attack and destroy foreign cells. Of course, cancer cells are not literally foreign but they often exhibit molecular changes that might allow the immune system to recognize the cells as being abnormal. Individuals treated with immunosuppressive drugs can develop many cancers. Most of the cancers that occur at increased rates in people with AIDS are caused by the viruses. 

Tumors are heterogeneous populations of cells that express different antigens. Those cells containing antigens that elicit a strong immune response are likely to be attacked and destroyed, while cells that either lack or produce smaller quantities of such antigens are more likely to survive and proliferate. So as tumors grow, there is a continual selection for cells that elicit a weaker immune response.

Some cancer cells produce molecules that kill or inhibit the function of T lymphocytes. Tumors may also surround themselves with dense supporting tissue that shields them from immune attack.

Cancer cells simply divide so quickly that the immune system cannot kill them fast enough to keep  

tumor growth in check. The larger a tumor grows, the easier it becomes to overwhelm the immune system. Cells with weaker immune response are selected for tumor growth. 

The tumor microenvironment influences tumor growth, invasion and metastasis.

Tumor behavior is influenced by interactions between tumor cells and the surrounding tumor microenvironment. For example, angiogenesis is triggered by growth factors released by tumor cells that act on normal endothelial cells in the surrounding tissue. Proteases produced by both facilitate invasion by degrading the components of ECM. Mobility and direction is influenced by signaling molecules. Penetration and then metastases is stimulated by growth factors.

The tumor microenvironment can also contain cells and molecules that hinder invasion and metastasis. For e.g., TGF-beta, a potent inhibitor of proliferation for many cell type. Sometimes even the cancer cells start secreting TGF-beta themselves, which inhibits the growth of surrounding normal cells and allows cancer cells to reproduce and invade surrounding tissues more rapidly because of the decreased competition from neighboring cells.