Metastasis Health Article

Definition

The ability to invade and metastasize are the defining characteristics of a cancer. Invasion refers to the ability of cancer cells to penetrate through the membranes that separate them from healthy tissues and blood vessels. Metastasis can refer either to the spread of cancer cells to other parts of the body, or to the condition produced by this spread. The English word metastasis (plural, metastases) comes from a Greek word that means "a change." The tumors produced by metastasis are sometimes called secondary tumors. Metastasis is responsible for 90% of the deaths caused by cancer.

Description

Metastasis is a complex multi-step process that begins with changes in the genetic material of a cell (carcinogenesis) followed by the uncontrolled multiplication of altered cells. It continues with the development of a new blood supply for the tumor (angiogenesis), invasion of the circulatory system, dispersal of small clumps of tumor cells to other organs or parts of the body, and the growth of secondary tumors in those sites.

Carcinogenesis and genetic mutations

The first step in cancer development is a change or mutation of the DNA in the chromosomes of a cell. Mutations can be triggered by a number of different factors, including:

• Environmental carcinogens. Ultraviolet radiation from the sun is known to cause skin cancer. Chemical carcinogens include tobacco smoke, asbestos, and benzene. Ionizing radiation from x-ray therapy or atomic fallout, or industrial exposure to uranium or thorium are also associated with an increased risk of cancer.
• Viruses. Infection by a virus containing an oncogene is known to cause cancer in experimental animals. In humans, such viruses as human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis B or C viruses, and Epstein-Barr virus (EBV) have been linked to Kaposi's sarcoma, anal cancer, certain types of lymphoma, primary liver cancer, and cancers of the genitals.
• Chronic irritation and inflammation. Chronic irritation of the skin, or chronic inflammation of the bladder or bile ducts caused by certain intestinal parasites, have also been linked to cancers of the skin, bladder, or pancreas.
• Chromosomal rearrangement or damage. Oncogenes are genes found in the chromosomes of tumor cells whose activation is associated with the conversion of normal cells into cancer cells. Oncogenes are sometimes activated by chromosomal rearrangements. The so-called Philadelphia chromosome, an abnormality that involves a transposition of genetic material between the long arms of human chromosomes 9 and 22, is found in about 80% of patients with chronic myelocytic leukemia.
• Loss of tumor suppressor genes. Another type of genetic alteration that can lead to cancer is the inactivation of anti-oncogenes, or tumor suppressor genes. Under normal circumstances, tumor suppressor genes act like a brake on cell growth and division. If these genes are altered or lost, oncogenes can stimulate cells to multiply uncontrollably without any opposition. In colorectal cancer, deletion of the DCC gene, which is a tumor suppressor gene located on the long arm of human chromosome 18, lowers the patient's chances of five-year survival by 30%.

Other mutations in a cell's DNA occur for reasons that are not yet fully understood.

Steps in the development of metastases

Cell alteration and replication

Most cancer cells originate within the epithelium, which is a layer of tissue that covers body surfaces and lines the inner surfaces of body cavities and blood vessels. Cancer cells in epithelial tissue are known to be genetically unstable and to have a high mutation rate. Most cancers, in fact, are the end result of multiple genetic alterations both in oncogenes and tumor suppressor genes. The activation of oncogenes is accompanied by the loss or deactivation of tumor suppressor genes, which means that that one of the body's normal lines of defense against uncontrolled cell proliferation is disabled just when it is most needed.

Following these alterations in its genetic material, the cell replicates, or copies itself at a faster rate. In some instances, a mutation prevents the cell's apoptosis, or programmed self-destruction. Apoptosis, which is also sometimes called "cell suicide, " normally occurs when a cell recognizes some damage to its DNA and dies. The protein produced by the p53 gene ordinarily encourages apoptosis in cells with defective DNA, but these cells are more likely to survive and replicate if the p53 gene has been altered or deactivated.

Breaking through the basement membrane

Once a cancer develops, the first stage in the development of metastasis is the tumor's penetration of the basement membrane, which separates epithelial tissue from underlying connective tissue. The basement membrane is a specialized layer of extracellular matrix, which is a mass of connective tissue fibers and proteins that support and nourish the body's connective tissues. Under normal circumstances, the extracellular matrix is a barrier that keeps cells from moving away from their sites of origin. Cancer cells, however, secrete several different types of enzymes that digest the proteins in the basement membrane. When the membrane has been sufficiently weakened, the tumor can push through it.

Angiogenesis

Angiogenesis is the process in which a tumor creates its own blood supply by releasing growth factors—particularly a substance called vascular endothelial growth factor, or VEGF—that attract vascular cells which begin to migrate toward the tumor. The vascular cells eventually form new blood vessels within the tumor. Angiogenesis is sometimes called vascularization, which means blood vessel formation. Angiogenesis is a significant step in the development of metastasis for two reasons: the formation of blood vessels in the tumor supplies the tumor with nutrients that speed up its growth; and these vessels also provide pathways for cancer cells to travel from the primary tumor to other organs. A similar process of vessel formation involves the lymph system.

Angiogenesis may occur at about the same time that the tumor breaks through the basement membrane, but it can also take place at an earlier point in the tumor's growth.

Invasion and embolization

After the tumor's new blood vessels have formed, individual cancer cells break off from the tumor and travel through these new vessels into the body's main circulatory system. These cells are sometimes called micrometastases. Even a small tumor can shed as many as a million cancer cells each day into the blood and lymph vessels. Most of these cells die soon after entering the blood stream or lymph vessels. Sometimes, however, the cancer cells may travel as small clumps of cells called emboli. A protein called fibrin, which is ordinarily formed when blood clots, surrounds each embolus. The fibrin appears to protect the embolus of cancer cells as it moves through the circulatory system, and may increase its chances for survival when it arrives in the capillaries (small blood vessels) that supply another organ or area of the body.

Extravasation and formation of secondary tumors

Extravasation refers to the cancer cell's breaking out through the wall of the capillary where it has been stopped and invading the tissue around the capillary. In order to extravasate, the tumor cell must attach itself to the wall of the capillary. Once it has attached itself, it can work its way through the tissue lining the blood vessel, the vessel wall itself, and the basement membrane covering the blood vessel. The tumor cell can then begin to replicate itself and start the process of angiogenesis, thus forming a metastasis or secondary tumor in its new location. The secondary tumor can eventually release its own cancer cells into the circulation and produce further metastases.

Most tumor cells do not survive in the blood stream long enough to extravasate and form metastases. The longer the cells are in the circulation, the more likely they are to die. The chances of a given tumor cell's surviving the journey and forming a metastasis in its new site have been variously estimated as one in 10, 000 or as less than one in a million. Researchers have asked whether the tumor cells that do produce metastases are random survivors or whether they have special capacities for survival and reproduction. Recent studies indicate that cells from the same tumor vary in their metastatic potential; those that eventually form metastases have a higher degree of malignancy.