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.
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 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.
Diagnosis and monitoring of metastases
Some primary cancers, such as lung and ovarian cancers, begin to shed tumor cells that form metastases elsewhere in the body before the primary cancer is large enough to be detected by standard diagnostic techniques. Marker molecules that are given off by micrometastases circulating in the bloodstream can now be detected.
Tumor markers are substances produced either by tumors themselves or by the body in response to a tumor. The blood levels of tumor markers can be used to evaluate the recurrence or spread of cancer and the patient's response to treatment. Some commonly used tumor markers include: prostate-specific antigen (PSA) for prostate cancer ; prostatic acid phosphatase (PAP) for prostate cancer that has metastasized, testicular cancer and leukemia; and CA 125 (Cancer antigen 125) for recurrence of ovarian cancer and also to detect cancers of the uterus, liver, pancreas, colon, cervix, lung, and digestive tract; as well as several others.
DNA analysis can be used to distinguish metastatic tumors from multicentric tumors. A multicentric cancer is one that appears simultaneously in several different parts of the body, as distinct from cancers with primary and secondary (metastatic) tumors. Mutations in the p53 tumor suppressor gene have been used as "genetic fingerprints" to identify differences between multicentric and metastatic tumors.
Some specific types of metastases
Metastatic tumors to the brain usually come to the doctor's attention in the same way as primary tumors—they cause increased pressure inside the head, disturbances of brain functions, or both. Common symptoms of brain metastases include headaches, seizures, loss of sensation or balance, or personality changes.
The most common source of brain metastases is primary cancer of the lung. Other primary sources include malignant melanomas and cancers of the breast, kidney, or digestive tract.
Secondary brain tumors are usually detected on either CT scans (computed tomography scans) or MRI studies (magnetic resonance imaging ).
If the patient has only one secondary tumor in the brain, it is sometimes possible to remove it surgically and then treat with radiation. Otherwise, radiation is used by itself to treat the tumors. Steroids may be given to reduce or lower swelling of the brain, treating the headaches and other symptoms. Chemotherapy has only a limited role in treating brain metastases, because most chemotherapy drugs cannot cross the blood-brain barrier. However, intrathecal chemotherapy (chemotherapy drugs injected directly into the spinal fluid) can have a role in treating brain metastases. Patients with multiple metastases in the brain or widespread cancer elsewhere in the body have a very poor prognosis. Treatments that are still under evaluation include laser-assisted surgery and biological response modifiers.
Primary bone cancers are less common than bone metastases. Bone metastases, in fact, are a common cause of pain in many patients with late-stage cancer. Metastases in the spine can compress the spinal cord and damage the nervous system. Bone metastases also make bones easier to fracture.
Breast, lung, and prostate cancer are responsible for about 80% of bone metastases; and over half of patients with these three types of primary cancer will develop bone metastases. Patients with lung cancer that has metastasized to bone live on average less than six months, but breast and prostate cancer patients may have lengthy periods of survival with bone metastases.
Bone metastases are usually caused by tumor cells carried through the bloodstream, and are typically multiple. About 70% of bone metastases occur in the ribs, spine, sacrum (lowest portion of spine, attached to pelvis), or head; most of the remainder occur in the long bones of the body.
Bone metastases are usually detected by bone scans, CT scans, or MRIs, and confirmed by a biopsy .
Bone metastases are treated with hormonal or systemic chemotherapy and/or radiation therapy . Metastases in the spine may require surgical removal of part of the vertebrae (laminectomy) followed by radiation treatment to prevent compression of the spinal cord. Surgery may also performed if there is a risk of fracture.
As of May 2001, two new drugs show promise as treatments for bone metastases. One is a generic drug called clodronate, which is taken by mouth, and the other is a medication called Atrasentan. Atrasentan was tested on patients in advanced stages of bone metastases who were no longer responding to other forms of treatment.
Metastatic tumors in the lungs may result either from primary cancer of the lung or from malignancies elsewhere in the body that spread to the lungs through the circulatory system or by direct extension. The incidence of metastatic cancer to the lung is six in 100, 000 people. Almost any type of cancer can metastasize to the lung, but the most common tumors that spread to the lung are breast cancer , sarcomas , non-Hodgkin's lymphoma , neuroblastoma , and Wilms' tumor . Between 20% and 54% of patients dying of cancer are found to have metastases in the lungs.
Diagnosis is usually the appearance of a group of masses on a chest x ray . Evaluation of lung metastases is first directed at diagnosing/locating the primary tumor.
Secondary lung cancers are treated primarily by appropriate systemic therapy for the primary tumor. Surgery for secondary lung tumors may be beneficial if there are four or less metastases. Surgical removal of tumors metastatic to the lung is usually performed only if: the primary tumor is treatable, all metastases can be removed, chemotherapy or other nonsurgical approaches cannot be used, and if there are no metastases elsewhere in the patient's body. If the primary cancer is a malignant melanoma , and there is only one secondary tumor, surgery may be an option. (Surgery is usually not done if the primary cancer is a malignant melanoma and there is more than one secondary tumor.) The five-year survival rate for surgical treatment of secondary tumors to the lung is 20%-35%.
The most common form of liver cancer is metastatic; in fact, metastases in the liver are often the first noticeable evidence of a primary cancer located elsewhere in the body. In the liver, finding multiple metastases is more common than finding a single tumor. The liver's important role within the circulatory system makes it a common stopping point for tumor emboli carried in the blood from other organs.
The most common sites of primary tumors that metastasize to the liver are the lungs, breasts, colon, pancreas, and stomach.
The diagnosis of metastatic liver cancer is usually difficult unless the patient's primary tumor is in advanced stages of disease. Ultrasound, CT scans, and liver function tests are used to screen patients with a known cancer for metastases in the liver, but the results are not fully reliable. A definitive diagnosis depends on biopsy of liver tissue.
As of 2001, metastatic cancer to the liver is considered incurable. Systemic chemotherapy may temporarily shrink tumors in the liver and extend the patient's life span but does not cure the cancer. Radiation treatment may relieve pain but is not otherwise helpful. Some doctors may recommend surgical removal of liver metastases, particularly if the primary tumor is in the colon and there is a solitary metastasis, but others do not favor this approach. The five-year survival rate for surgical removal of liver metastases is 20%-30%.
Metastatic cancers of unknown primary origin
Between 0.5% and 7% of all cancers are carcinomas of unknown primary origin, or CUPs. The patient's history and physical examination should be analyzed for signs of breast, prostate, pelvic, rectal, and gastrointestinal cancers . The pattern of spread of a CUP may indicate whether the primary tumor is above or below the diaphragm; lung metastases are twice as common with primary tumors found to be above the diaphragm, while liver metastases are more common if the primary site is below the diaphragm.
Metastases of unknown primary origin are usually treated by chemotherapy— either cisplatin/carboplatin , doxorubicin or paclitaxel . In most cases, the patient's prognosis is poor; the average length of survival is three to four months, with fewer than 10% of patients surviving five years. Male sex and involvement of the liver are negative factors in the prognosis.
Surgery as a method of cancer treatment has limitations in the therapy of metastatic cancer. It is sometimes used to remove large secondary tumors that are causing pain or interfering with body functions. It also may offer a survival advantage over other therapies, as with limited metastases to the lung or liver.
Chemotherapy is frequently used to treat micro-metastases that have entered the patient's bloodstream or lymphatic system. Systemic chemotherapy is the only type of treatment that can act at multiple sites simultaneously. Because of some chemotherapy drugs' side effects and risks (for example, nausea and vomiting , some drugs are implicated in causing some cancers), the likelihood of tumor responsiveness needs to be balanced with the patient's quality of life when selecting chemotherapy.
Radiation therapy can be effective in the treatment of metastatic disease, especially for metastases to the brain and bones. It is limited, however, because it treats only a limited area. One complication that is possible with radiation therapy is that it has been associated with an increased rate of secondary cancers in patients who have been previously treated for malignancies. The risk is particularly high in patients who were treated with a combination of radiation and chemotherapy.
Immunotherapy, or immunologic therapy , is a modality, or method, of cancer treatment that is still in its experimental stages. It mobilizes the patient's own immune system to fight cancer cells. Immunotherapy is being evaluated in the treatment of metastatic melanoma, renal cell carcinoma , breast tumors, and other tumors. Some of the substances that are being tested in clinical trials are produced by the human body, while others are made in laboratories. The major categories of substances used in immunotherapy include:
- Interferons . Interferons are proteins produced by virus-infected cells that limit further reproduction of the virus and stimulate resistance to the infection.
- Interleukins. Interleukins are small proteins that promote the growth and activation of the body's white cells. Interleukin-2, known as IL-2 or aldesleukin , is approved for the treatment of metastatic melanoma and renal cell carcinoma.
- Tumor necrosis factor (TNF). TNF is a protein that was discovered in 1975. It destroys cells that show unusually rapid growth and stimulates the production of inter-leukins.
- Monoclonal antibodies . Monoclonal antibodies are antibodies produced in laboratory-grown cell clones in order to achieve greater abundance and uniformity than are found in antibodies produced in the body.
- Vaccines . Cancer vaccines are intended to stimulate the body's killer T-cells (a specialized type of white blood cell) to attack tumor cells. Some vaccines being tested are made from relatively rare white blood cells called dendritic cells; others are made from genetically altered tumor cells.
Newer therapies for metastatic cancer
Recent advances in understanding the process of metastasis have led to some new approaches to treatment.
Some researchers are investigating ways to replace a mutated p53 tumor suppressor gene, or to inhibit an activated ras oncogene. Another approach involves the use of angiogenesis inhibitors to suppress metastatic tumors. An antibody to VEGF, called anti-VEGF, is presently being used in clinical trials for patients with late-stage colon, breast, and lung cancers. A second angiogenesis inhibitor that is being tested is endostatin.
Other researchers are studying substances that trigger apoptosis in defective cells or prevent the uncontrolled multiplication of tumor cells.
Isolated perfusion is the treatment of metastatic melanoma and sarcoma to the extremities by isolating the vasculature (blood vessels) of the affected extremity, and then delivering high doses of chemotherapeutic drugs directly to the area of metastatic disease. The limb is then flushed before re-establishing circulation. With this technique, it becomes possible to deliver doses of drugs regionally that would otherwise be very toxic or lethal if delivered systemically.
Hyperthermia is the use of therapeutic heat to treat cancers on and inside the body. The goal of hyperthermia is to shrink and destroy cancer without harming noncancerous cells. The treatment can be delivered directly to the tumor, to an area of the body, or to the whole body. Research has established that the effectiveness of some forms of radiation therapy and chemotherapy are enhanced when combined with hyperthermia. In 2001, the American Cancer Society acknowledges that hyperthermia can make the cancer cells of some cancers more responsive to treatment, but still considers the treatment experimental, especially in whole-body form. The National Institutes of Health are sponsoring ongoing clinical trials studying hyperthermia. Patients with extensive metastasis may not be good candidates for hyperthermia.
Alternative and complementary therapies for metastatic cancer
The National Center for Complementary and Alternative Medicine (NCCAM) is sponsoring new as well as ongoing trials of alternative treatments for metastatic cancer. One ongoing trial involves PC-SPES , a combination of eight Chinese herbs that is used to treat prostate cancer. Other trials are evaluating the use of herbal remedies to treat the side effects of chemotherapy. The National Cancer Institute (NCI) makes information about ongoing clinical trials available. Patients can contact the NCI or the NCCAM at the numbers and web sites listed below.
See Also Cancer biology; Cancer genetics; Hepatic arterial infusion; Carcinogenesis
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NIH National Center for Complementary and Alternative Medi cine (NCCAM) Clearinghouse. P. O. Box 8218, Silver Spring, MD 20907-8218. TTY/TDY: (888) 644-6226. Fax: (301) 495-4957. Web site: <http://www.nccam.nih.gov>.
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Rebecca J. Frey, PhD
—The process of forming new blood vessels that supply a tumor with nutrients and help to carry tumor emboli into the larger vessels of the circulatory system.
—The programmed self-destruction of a cell, which takes place when the cell detects some damage to its DNA. Apoptosis is sometimes called "cell suicide."
—A specialized layer of extra-cellular matrix that separates epithelial tissue from underlying connective tissue. Cancer cells must break through the basement membrane in order to migrate to other parts of the body and form metastases.
Embolus (plural, emboli)
—A clump of tumor cells that breaks off from a primary tumor to travel through the circulatory system and lodge in a capillary in another part of the body. The process of forming emboli is called embolization.
—The layer of tissue that covers body surfaces and lines the internal surfaces of body cavities, blood vessels, and hollow organs. Most cancer cells arise within epithelial tissue.
—A collection of connective tissue proteins and fibers that supports and nourishes body tissues. The extracellular matrix forms a physical barrier to the movement of tumor cells.
—The process of reverse invasion in which tumor cells that have invaded the blood vessels and traveled to other organs force their way back out of the blood vessels and into the tissues surrounding their new site.
Micrometastasis (plural, micrometastases)
—A term sometimes used to describe malignant tumor cells circulating in the blood or other metastases too small to be detected by a standard clinical examination.
—A type of cancer that appears at several different sites in the patient's body simultaneously.
—Any gene that is a factor in triggering the development of cancer. Oncogenes are mutated forms of proto-oncogenes, which are genes that promote the normal process of cell growth and division.
—The process in which a cell duplicates or copies itself.
—Substances that occur in the blood, urine, or tissues of patients with certain types of cancer. Tumor markers may be produced either by the tumor itself or by the body in response to the tumor.
Tumor necrosis factor (TNF)
—A protein that destroys cells showing abnormally rapid growth. TNF is used in immunotherapy to shrink tumors rapidly.
Tumor suppressor gene
—A gene that encodes proteins that inhibit cell division and replication. Tumor suppressor genes are damaged or inactive in many types of cancer cells.
Vascular endothelial growth factor (VEGF)
—A substance released by tumor cells that attracts vascular (blood vessel) cells to the tumor. The vascular cells then form new blood vessels within the tumor.
—Another name for angiogenesis.
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me·tas·ta·sis / məˈtastəsəs/ • n. (pl. -ses / -ˌsēz/ ) Med. the development of secondary malignant growths at a distance from a primary site of cancer. ∎ a growth of this type. DERIVATIVES: met·a·stat·ic / ˌmetəˈstatik/ adj.
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—metastatic (met-ă-stat-ik) adj.
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