Why are metastatic tumors more dangerous than primary tumors?

In most cases, a single primary tumor arises in an organ. If there is only one tumor, and it can be detected and removed, the cancer is completely eradicated. In addition, some primary tumors form in organs that are not essential for survival such as the prostate and breast. Even if there are several primary tumors in those organs, the entire organ could be removed without threatening the life of the patient. Single primary tumors are only fatal if they arise in an essential organ such as the brain or pancreas and rapidly invade throughout that organ. When tumors metastasize, they often do so over an extended period of time and each single tumor cell that reaches another organ can give rise to a new tumor. It is common to see hundreds of metastatic colonies arise in an organ that is distant from the primary site. As these multiple colonies each grow larger, they can take over the function of the entire organ and render it useless. The three most common sites of tumor metastasis are the lungs, liver and bone marrow - all essential organs which must function for a person to survive. <top>

How do tumor cells metastasize?

Carcinoma In Situ. The process by which metastases form is now well understood. Most human tumors are carcinomas which originate in the epithelial layer of a given organ. The first stage of tumor growth is generally the formation of a small sphere of tumor cells. When this sphere reaches a size of 1-2 millimeters in diameter the cells on the inside begin to die because they cannot get sufficient nutrients from the environment. Because the cells on the outside of the sphere continue to divide while the cells on the interior are dying, the tumor sphere can remain at the same size and in the same place (carcinoma in situ) for months or years without changing. We now know that most 'healthy' people have numerous small tumors of this type in organs such as the thyroid, breast , prostate and cervix that never grow large and never harm the individual.

Primary Tumor

Local Invasion and Angiogenesis. To grow beyond a small sphere, tumor cells must be able to invade across a barrier called the basement membrane and into the local tissue. At this point they also must be able to produce factors that recruit new blood vessel formation (angiogenesis)(Zetter BR. Angiogenesis and Tumor Metastasis, Ann Rev Med. 1998:). The most potent tumor angiogenesis factors are fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). This results in a large vascular network that surrounds the tumor and promotes the expansion of the tumor to a larger size. In addition to allowing the tumor to grow larger, these new vessels also support tumor metastasis. The vessels promote metastatic spread (dissemination) by providing the route of exit for cells to leave the primary tumor and circulate in the blood stream for travel to distant sites. It has been estimated that a tumor the size of a grape (1 centimeter in diameter) can shed as many as 2,000,000 cells into the circulation in a 24 hr period by means of the new angiogenic blood vessel network.

Invasion	Angiogenesis	Intravasation

Circulating Tumor Cells. The tumor cells that enter the new tumor blood vessels will circulate in the blood stream until they are either killed, trapped in a capillary bed in another organ, or pass across the blood vessel wall (extravasate) into the tissue in a distant organ. It is only these latter cells that take exit the bloodstream and enter a new tissue that can ever form metastatic colonies. Cells that stay in the bloodstream or get trapped inside small vessels will die fairly rapidly (often within hours). Only a small percentage of the cells that reach the bloodstream ever form metastatic colonies (as few as 1 in 100,000) but because the process takes place over and over each day, there can eventually be several hundred metastatic colonies in a single organ.

Adhesion to Blood Vessel Wall in Distant Organ	Extravasation and Migration

Lymphatic Metastasis. In many cases the first metastases detected in cancer patients consist of tumor cells that have spread to regional (local) lymph nodes. Lymphatic metastases indicate that the tumor has acquired the ablility to leave the primary site and often suggests that distant metastases will later be found. Thus the prognosis for patients with no lymphatic metastases is better than for those who have one or pore postivie lymph nodes. It is important to realize, however, that lymphatic metastases are rarely themselves the cause of death in cancer patients. As mentioned earlier, cancers are most dangerous when they spread large numbers of metastatic colonies to critical distant organs such as the liver, lung, bone or brain. Thus the prognosis for patients with known distant metastases is often worse than for those patients who display only regional lymphatic metastases. Micrometastases and Tumor Dormancy. The single cells that initiate the formation of tumor metastases often start out by producing small colonies, consisting of several cells that wrap around a small blood vessel in the new organ site. Again these colonies are limited by diffusion to 1-2 millimeters in diameter. In some cases, the colonies quickly progress to a large size and rapidly take over the organ. In other cases, the tumors remain small for months or even years. A patient can live their entire life expectancy with multiple small metastases in place as long as none of them exceed this small size. However, in some cases, a metastatic colonies may stay small and dormant for several years and then rapidly start to expand and result in the death of the patient. Current thinking holds that new therapies could be designed to keep metastatic colonies small and dormant without actually eliminating every tumor cell in the body. One approach is to use long-term treatment with anti-angiogenic drugs to keep the metastatic colonies avascular (no new blood vessels) which may keep them small and harmless.

Micrometastasis	Metastasis

How do tumor cells become capable of metastasis? The notion of tumor progression.

One of the main interests in our lab is the process of tumor progression. This refers to the development of the properties required for a tumor to produce metastatic colonies in distant organs. It is generally agreed that tumor progression occurs over a long period of time and is generated primarily by mutations in the tumor cell DNA that accumulate with time. It is clear that the mutation rate is significantly higher in tumor cells than in normal cells. Some of the increase in mutation rate is due to congenital (hereditary) or spontaneous defects in DNA repair enzymes leading to unfaithful DNA copying. Although certain events in the metastatic process must precede others (for example, angiogenesis precedes tumor cell escape from the primary tumor), it is generally thought that the mutations responsible for this process accumulate randomly. Consequently, the development of any particular part of the metastatic process (invasion, migration, angiogenesis, etc.) must await the accumulation of the appropriate mutations that can permit that event to happen. <top>

Cancer Diagnosis and Prognosis

Despite the fact that most mutations do occur randomly as tumors progress to the metastatic state, some mutations are indeed associated with a particular stage in the metastatic process. For example, changes in cell proliferation often are among the earliest changes found in new tumors, long before the tumors become metastatic. Alterations in cell-cell adhesion, and protease production often are seen after the changes in proliferation but before metastasis is observed because they are required for cell invasion across the basement membrane and into the tissue stroma. Other mutations may be seen later in tumor progression as the cells are becoming or have become capable of metastasis.

Could the distinction in the time of appearance of a particular mutation be useful clinically? We believe that it is. For example, if we wish to know if a particular patient has or does not have cancer, we should use a marker that comes up very early and is expressed continuously by the tumor. In this way, all patients with that cancer will be detected by screening for that marker. In contrast, a marker that comes up when a tumor is converting from non-metastatic to metastatic may be useful in tumor prognosis. A patient without evidence of that marker may have tumor that is still confined to the primary site and can be eliminated by radiation or surgery. In contrast, a tumor that produces a metastatic marker may have already produced micrometastases at a distant site and require systemic treatment with chemotherapy or anti-angiogenic agents. Markers produced by aggressive tumor cells may also be used to immunize patients (tumor vaccines) and use the body's immune system to attack the aggressive tumor cells.

In our own lab, we have found that certain molecules that regularly appear later in metastatic progression can be used to predict the course of prostate cancer in patients. The PSA test, which can be used to diagnose prostate cancer is not as useful for telling whether a patient will go on to develop metastatic disease. In contrast, we have developed a panel of markers that appear to be able to predict which tumors are likely to go on to metastasize or have likely already produced metastatic colonies. The prototype for this type of molecule is thymosin Beta-15. A molecule that stimulates cell migration and promotes metastasis in prostate cancer cells. We and others have now shown that tumors in which thymosin Beta-15 cannot be detected are unlikely to develop metastases and may not warrant aggressive treatment. In contrast, tumors expressing thymosin Beta -15 are more likely to have disseminated metastases and are candidates for aggressive systemic therapy. A more complete description of this molecule can be found in the section of this web site devoted to prostate cancer.