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Spread of Cancer through the Lymphatic System

(Summer 2011 - Reprinted from Cancer Quest / Emory University / Winship Cancer Institute http://www.cancerquest.org )

The Lymphatic System

The lymphatic system plays an important role in controlling the movement of fluid throughout the body. Specifically the lymphatic system controls the flow of lymph, a colorless fluid containing oxygen, proteins, sugar (glucose) and lymphocytes (cyte=cell). Once they are formed in the bone marrow, lymphocytes circulate in the body and reside in lymphatic tissue including lymph nodes and the spleen, where they search for and await contact with their target proteins. The lymphatic system is a system of vessels (tubes) that is present all throughout the body. Like the more familiar circulatory system, the lymphatic system carries fluid, proteins and cells of the immune system.

Red blood cells are not found in the lymphatic system. The two systems (lymphatic and circulatory) are connected. The lymphatic system picks up fluid and cells from around the body and returns them to the circulatory system via ducts located in the neck/shoulder area. The fluid within the vessels is known as lymph. There are some similarities and differences between the (more well known) circulatory system and the lymphatic system.

Small lymphatic vessels merge into larger ones and these large vessels eventually empty into lymph nodes. Lymph nodes are kidney bean shaped tissues that are found in grape-like clusters in several locations around the body. Lymph nodes are sites of immune system activation and immune cell proliferation (growth). The fluid in this extensive network flows throughout the body, much like the blood supply. It is the movement of cancer cells into the lymphatic system, specifically the lymph nodes, that is used in the detection of metastatic disease.

Spread of Cancer Through the Lymphatic System

The lymphatic system is of great importance in cancer for several reasons:

Cancer cells can spread (metastasize) by getting into the lymphatic system.
Many cancer types are classified or staged by whether or not cancer cells can be found in lymph nodes close to the site of the original tumor. The logic is this: The lymphatic system is found all over the body so if cancer cells from a tumor have made it that far, they may also have traveled to distant locations.

When a cancer cell has moved through the blood or lymphatic systems or via direct contact to another location, it may divide and form a tumor at the new site. Metastatic tumors often interfere with the functions of the organs involved and lead to the morbidity and mortality seen in cancer.
The lymphatic system plays a crucial role in the metastasis of certain cancers. Lymphatic vessels are designed for entry and exit of immune cells, and are therefore easy for tumor cells to enter. In addition, the flow of lymph is quite slow, so there is little stress to harm cells.⁽¹⁾ Researchers originally believed tumor cells invaded the lymphatic system by eroding the vessel walls as the tumor advanced and metastasis would then occur by passive drainage. However, current evidence suggests the interactions between metastasizing cells and lymph vessels are much more active and complex, and specific interactions between the two are required.

The presence of metastases in lymph nodes near the primary tumor often indicates metastasis to distant organs, and is a significant prognostic indicator in many cancers. To assess the presence of metastasis to surrounding lymph nodes, physicians perform a lymph node biopsy. In this procedure, the lymph nodes are removed by surgery and are checked for the presence of cancer cells. Nodes are determined either positive or negative for cancer.

Because lymph drainage pathways from a tumor vary greatly between patients, even for the same area, up to 30% of tumors cannot be accurately predicted to migrate to specific lymph nodes. Improvement in lymphatic imaging and mapping are needed to ensure that metastasizing cancers are not accidentally missed. ⁽²⁾

The diagram below shows the lymphatic system

lymph vessels and nodes

Kopfstein, L., and G. Christofori. 2006. Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment. Cell Mol Life Sci. 63:449-68. [PUBMED]
Shayan, R., M.G. Achen, and S.A. Stacker. 2006. Lymphatic vessels in cancer metastasis: bridging the gaps. Carcinogenesis. 27:1729-38. [PUBMED]

Routes of Metastasis

There are three primary ways tumors can spread to distant organs:

Through the circulatory (blood) system (hematogenous)
Through the lymphatic system
Through the body wall into the abdominal and chest cavities (transcoelomic).

The circulatory system is the primary route of spread to distant organs, while lymphatic vessels provide a route to local lymph nodes, after which metastases often travel through the blood ⁽¹⁾ While the circulatory system appears to be the most common route, the extent of lymphatic versus hematogenous spread appears to depend on the origin and location of the primary tumor.⁽²⁾ For example, bone and soft tissue tumors (sarcomas) spread primarily through the blood, while melanoma, breast, lung and gastrointestinal tumors spread through the lymphatic system.⁽³⁾ Transcoelomic spread is fairly uncommon, and appears to be restricted to mesotheliomas and ovarian carcinomas.⁽⁴⁾

In order for tumor cells to gain access to lymphatic or blood vessels, tumors need to promote the growth of these vessels into and around the tumor. Growth of blood vessels is called angiogenesis, and growth of lymphatic vessels is lymphangiogenesis.

Bacac, M., and I. Stamenkovic. 2008. Metastatic cancer cell. Annu Rev Pathol. 3:221-47. [PUBMED]
Gerhardt, H., and H. Semb. 2008. Pericytes: gatekeepers in tumour cell metastasis? J Mol Med. 86:135-44. [PUBMED]
Kopfstein, L., and G. Christofori. 2006. Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment. Cell Mol Life Sci. 63:449-68. [PUBMED]
Tan DS, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol. 2006 Nov;7(11):925-34. [PUBMED]

Treatments that Target Metastasis

Metastatic Suppressors

Recent work has uncovered a group of molecules that act to induce or suppress metastasis without affecting the growth of the primary tumor. Many molecules, termed Metastatic Suppressors, have been identified. These molecules are critical for different stages of metastasis, and may function to inhibit cell death upon loss of cell adhesion, or enhance the ability of cells to migrate through the stroma. Researchers are hopeful that these molecules may prove valuable as anti-cancer/anti-metastasis targets.⁽¹⁾
It is important to realize that the majority of current anti-cancer drug studies are conducted using primary or cultured tumor cells, and the efficacy of each drug is measured by its ability to reduce the size of primary tumors or kill cells being grown in laboratories. However, because metastatic suppressors do not affect growth of the primary tumor, it is likely like many potentially useful anti-metastatic drugs have been overlooked. New methods of analyzing the ability of drugs to inhibit metastasis, rather than primary tumor growth, are being developed, and should lead to a useful new class of therapeutic compounds.⁽²⁾

Anti-angiogenesis Therapy

Because metastasis relies on the growth of new blood vessels in both the primary and secondary tumors, drugs that inhibit angiogenesis may inhibit metastasis. Currently, the combination of anti-angiogenesis drugs with chemotherapy/radiation is the most effect treatment. Unfortunately, many tumors become resistant to the anti-angiogenesis treatment, so this is generally not a longterm solution. ⁽³⁾

Current research into inhibiting metastasis is focusing on understanding which step of metastasis is the most amenable to therapy. The identification of metastatic suppressor genes has opened up many exciting new potential targets for preventing and inhibiting this deadly event.

Stafford, L.J., K.S. Vaidya, and D.R. Welch. 2008. Metastasis suppressors genes in cancer. Int J Biochem Cell Biol. 40:874-91. [PUBMED]
Steeg, P.S. 2006. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 12:895-904. [PUBMED]
Gupta, G.P., and J. Massague. 2006. Cancer metastasis: building a framework. Cell. 127:679-95. [PUBMED]