Metastasis: For the Scientist

 

Welcome to the Metastasis Research Society

Note to Members:

All MRS memberships are per calendar year. If you are a member, go to the payment page to ensure uninterrupted access to the website and access to the MRS Official Journals -- Clinical & Experimental Metastasis and Cancer & Metastasis Reviews. If you are not yet a member, submit your application membership form today.

The definitions:
The semantics of describing metastasis are crucial to understanding and communication on this disease process. A brief review of the metastasis vocabulary can be found here: primary tumor; secondary site; metastatic cascade; dissemination; metastasis; metastatic site; metastatic processes; systemic disease; invasion; cell motility; cell migration; tumor-host interaction; tumor microenvironment; pre-metastatic niche; metastatic lesion; colonization; staging; targeted therapy (put in table)


 

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Objective: 1) work along defined aspects of the metastatic cascade, 2) with predefined vocabulary, 3) incorporating relevant references and links, 4) keeping the main page simple with links to subpages that provide greater detail.


The Primary Tumor


Local Invasion


Dissemination

neuronal 

other

Vascular

lymphatic

hemopoietic


Intravasation


Arrest


Extravasation


Dormancy


Active metastatic disease


Clinical manifestation


Treating metastatic disease


 

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The Metastasis Research Society is dedicated to understanding the process of tumor metastasis on a cellular, molecular and biochemical basis; to the identification of potential therapeutics that would halt the metastatic process and their preclinic evaluation; and to working with clinicians to design and implement clinical trials to bring these new therapeutic strategies forward.

 

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).

 

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.

 

Growth in the distant site is called metastatic colonization. We know less about this process than the previous steps . While a tumor, by definition, can grow, 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. 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 congenial soil. Thus metastatic tumor cells need to have an environment which supports their growth. This can result from some very general factors in the blood stream that could aid growth virtually anywhere (examples are cytokines such as TGF-b and phospholipids such as LPA).  Tumor cells must establish a blood supply (angiogenesis) to continue to grow. Alternatively, there are many tissue specific environments that may promote tumor colonization. One of the best studied is in bone metastasis. Here a “vicious cycle” has been described where tumor derived factors stimulate the osteoclasts in the bone to degrade the bone matrix; when degraded, the bone matrix releases factors that stimulate tumor cell growth, providing a never ending cycle.

 

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 defences 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.

 

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.