Understanding Metastasis

Introduction

Our current understanding of metastasis is in large part based on landmark discoveries from the past two decades.  A brief description of cancer metastasis is provided below. A YouTube video is available that visualizes the process.

What is metastatic cancer?

Tumor metastasis (from the Greek “change of place”) is the movement of tumor cells from the site where the cancer began, to grow in other sites of the body. It is a complex process that is only partially understood today at the biochemical and molecular levels. When a cancer patient wakes from surgery and asks “Has it spread?”, they are asking if the tumor has metastasized. For many cancers, surgery and radiation therapy remove or destroy the the primary tumor. It is the spread of cancer cells to other (secondary) sites and their growth in these sites that can contribute to some cancer patients’ sickness (morbidity) and deaths (mortality).

The tumor metastatic process has been compared to a marathon. Tumor cells have to invade the solid tissues around the primary tumor site. The tissue in which the tumor arose is complex, containing other cells such as fibroblasts, a protein filled matrix that provides a solid support and immune cells and lymphatic drainage. Tumors have to invade past these barriers.  To do so they develop the ability to move. Tumor cells do not float out of a tissue, they crawl. Basically, tumor cells react to factors in their environment, they put out a “finger” of the cell toward the attractant and ratchet the cell forward. To move, tumor cells must alter their adhesion to other cells and to the protein matrix in a very dynamic fashion. They may also have to create a pathway amongst the tissue, by degrading the protein matrix using enzymes (proteases).

Is it likely that a cancer will become metastatic?

Fortunately for us, the metastatic process is very inefficient. Researchers using experimental models estimate that 0.01% of the tumor cells that enter the bloodstream eventually form a metastasis. However, it remains difficult to determine when-or-if a cancer will become metastatic. Consequently, every cancer is evaluated for its risk of becoming metastatic and patients are treated accordingly. An advanced stage cancer is more likely to metastasize and is treated more aggressively then an early stage benign cancer.

How does metastatic cancer spread?

Tumor cells can spread around the body using one of two major “highways”. All tissues are served by blood vessels (which provide oxygen and nutrients) and also lymphatic vessels which drain excess fluid to nearby lymph glands. For many cancer cells, their first opportunity to escape is to use the lymphatic drainage system. This is why for many cancers lymph nodes are biopsied or removed at surgery to see if the cancer has spread, and oncologists us the information to determine the “stage” of the cancer. Cancer cells can enter the bloodstream either indirectly via the lymphatics, or directly from a vessel in the primary tumor. The bloodstream is a very harsh environment with a high velocity of flow and full of immune cells. Moreover, cancer cells are used to being attached to the proteinaceous matrix, many tumor cells die when detached from their support and have to swim ( detachment mediated death is called anoikis, another Greek word describing the death of leaves from as they detach from trees in the Fall). The majority of tumor cells get stuck (arrest) in the first capillary bed that they float into. This is why colon cancer tends to metastasize to the liver, etc. This is not always the case, however, and some tumor cells end up in distant organs. How do tumor cells get out of the bloodstream? In essence, they attach to the endothelial cells lining the blood vessels and the endothelial cells retract, they move apart, to permit the tumor cells to enter the tissue. This may be a normal reaction of endothelial cells to immune cells, cells of our immune systems migrate in and out of the bloodstream all the time to maintain surveillance. In fact, tumor cells can disguise themselves as lymphocytes by expressing similar molecules on their surface that fool the endothelial cells. These molecules may also determine their apparent ability to “home” to specific organs preferentially, as they may respond to gradients of chemicals differentially expressed there.

What happens after the cancer spreads to other organs?

Upon arriving in a distant organ, a metastatic tumor can grow and form, what is called, a secondary tumor or metastatic lesion. We know less about this process than the previous steps. While a tumor, by definition, can grow almost indefinitely, the growth in the primary tumor site is not always identical to growth elsewhere. In the primary tumor site, growth may have been aided by specific factors in the matrix or by interactions with specific neighboring cell types. When a tumor arrives in a new organ, it has to establish new interactions with the local tissue.

About 100 years ago, a British pathologist named Dr. Stephen Paget described metastasis by a “Seed and Soil” hypothesis. He proposed that flowers send seeds everywhere (just as tumor cells disseminate everywhere), but that seeds only grow in receptive soil. Thus metastatic tumor cells need to have an environment which supports their growth. A successful metastatic cells establishes a unique relationship with surrounding tissue called a “tumor-host interaction. Tumor cells release chemical signals that elicit a positive and supportive response from the surrounding tissue.  Tumor cells must establish a blood supply (angiogenesis) to continue to grow. The best described tumor-host interaction is found in the metastasis of breast and prostate cancer metastasis to bone. Once in the bone, the tumor cells initiate a cycle where the tumor cells release agents that promote degradation of the bone and this, in turn, promote tumor growth. This ultimately results in growth of the metastatic tumor and degradation of the bone.

Not all metastatic tumor cells that arrive in a distant organ go on to form a metastatic lesion. In fact, most of them don’t. The metastatic colonization process can be halted or retarded by a poorly understood process called tumor dormancy. Essentially, tumor cells can stay alive, but stop dividing; alternatively they can die (apoptosis) at rates equal to their proliferation, so that the small tumor fails to increase in size. There are probably many reasons for tumor dormancy. For instance, a lack of angiogenesis may cause dormancy, where a lack of an adequate blood supply may fail to provide sufficient oxygen and nutrients for growth. The environment of the metastatic site (matrix and other cells) may also enforce dormancy, or localized host defenses and immune responses may also contribute. We have a very incomplete understanding of the conditions that promote dormancy or bring a tumor cell out of this state. The breaking of dormancy is why some cancers recur 20-30 years after they were initially treated.

What are my treatment options?

It remains extremely challenging to treat metastatic cancer and the anti-metastasis therapies are drastically different for each individual cancers. Therefore, all options must be reviewed with informed medical professions. While tumor cells in a metastatic location were originally derived from the primary tumor of the originating organ, their relative response to treatment can be dramatically different. In fact, many tumor cells in the metastatic site do not respond to the treatment that is effective for the primary tumor. Currently the only means to prevent metastasis is the removal of the original (primary cancer). The treatment of existing metastases is subject to numerous variables and should be discusses with an informed medial professional.

Where do I find help?

Individuals that are concerned about their health status should seek help with their physician. Cancer is a complex disease and its metastatic dissemination requires rapid and complex intervention. Since cancer is a progressive disease, it is important to act timely and seek help now rather than wait. Besides consulting a physician, it is important to become informed on the specific disease, because each cancer behaves and is treated differently. The internet can be an excellent source of information but such information should be discussed with supporting medical council whenever possible.

For many patients, cancer is a chronic, life-long disease. Fortunately, treatments are improving and many cancer patients are living with their disease rather than dying of it. Nevertheless, the diagnosis, treatment, and subsequent life changes can be challenging. Many patients find great benefit in developing a support network that includes their family, friends, and patient-support advocates from a variety of agencies that have a unique understanding of the challenges faced by a cancer survivor. Patient-support advocates can be found in all major medical facilities that provide treatment for cancer. In addition there are several cancer-specific organizations that can either provide support or help identify those options.