What is the pathophysiology of brain metastasis?

Updated: Aug 01, 2018
  • Author: Victor Tse, MD, PhD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

To metastasize, tumor cells have to gain access to the circulation, survive while circulating, pass through the microvasculature of the adopted organs, extravasate into the organ parenchyma, and reestablish themselves at the secondary site. This process requires the tumor cells to penetrate the basement membrane and cross the subendothelial membrane. Tumor cells achieve this by producing proteolytic enzymes, particularly metalloproteinases and cathepsins to help them to break down the basal matrix and enhance their invasiveness. Tumor cells modulate the expression of fibronectin, collagen, or laminin, and change the type of integrin receptor on their surface and on the surface of the surrounding stromal cells, resulting in desegregation of the stromal cells and creating a permissive environment for them to expand and invade.

Invading cells detach from the tumor mass, disperse, and traverse the epithelial/endothelial boundary; they will use the vascular conduit to colonize distant organs. Furthermore, they have to survive intravascular circulation and avoid immune surveillance during this journey. They accomplish that by coating themselves with a shield made out of the coagulating elements such as fibrin and platelets in the blood. These metastatic emboli also produce adherens to slow themselves down to a halt in the blood stream. These adheren molecules allow the circulating cancer cells to reattach onto the vascular wall and gain entry to the host tissue by disruption of the endothelial barrier. This leads to re-establishment of distant micrometastasis.

Tumor cells can survive in environments of low oxygen tension. When a tumor increases in volume by more than 2-3 times, the tumor expresses angiogenic factors such as angiopoietin-2 and vascular endothelial growth factors. These angiogenic modulators promote sprouting of surrounding blood vessels, which results in tumor angiogenesis. Additionally, these paracrine factors influence the readiness of target organs to accept tumor growth to prepare a favorable microenvironment for the tumor to undergo exponential growth and become a macrometastasis. [2]

Different tumors metastasize preferentially to different organs. Cells with similar embryologic origins are generally believed to have similar growth constraints and express similar sets of adhesion molecules, such as addressins. An example is melanoma; the cells are closely related to CNS cells (they are derived from the neural crest cells), and melanoma commonly metastasizes to the brain. Certain cell-surface markers in cancer are indicators and/or predictors of distant metastasis, eg, nm23 and CD44 in breast cancer. [3] Similarly, breast cancer cells that are HER positive are more likely to metastasis to the brain. [4] Renal, gastrointestinal, and pelvic cancer tend to metastasize to the cerebellum, whereas breast cancer is more commonly found in the posterior pituitary. Thus, the trafficking of cancer cells to their final destination is not entirely random and may be guided by factors produced by stromal cells of their host organ.

Recently, it has been shown that metastases may have originated from cancer initiating cells, which are more resistant to therapy by virtue of their stemlike properties. [5] Additionally, cancer cells recruit bone marrow–derived cells to modify the microenvironment of distant recipient sites, forming a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor. [6]

Cancer cells have been shown to recruit bone marrow—derived cells to modify the microenvironment of distant recipient site; the formation of a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor. [7]


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