Zetter Research Laboratory
Cell Migration in Tumor Metastasis
Work by our lab and by others has shown that metastatic tumor cells generally migrate at a faster rate than normal cells or non-metastatic tumor cells. This observation leads to the hypothesis that increased cell motility (migration) is necessary for cells to become metastatic. Why should cells require increased movement in order to succeed at generating metastases? There are several steps in the process of metastasis that could benefit from increased migration.
To invade into local tissue at the primary site, tumor cells must move away from the primary sphere of tumor cells. Only the single cells can move, not the whole tumor spheroid. To penetrate the barrier (basement membrane) that separates a tumor from the blood vessel-rich connective tissues, the tumor cells must move individually across this membrane in an invasive process that requires degradation of connective tissue along with movement through the tissues.
Once the tumor cells begin to grow in the connective tissues, they recruit new blood vessels to grow toward the tumor. The tumor cells must then migrate across the vessel wall and into the blood vessel where they are carried in the blood stream to distant sites. The process of entry into the blood vessels is called intravasation.
Tumor cells that can survive in the circulation must exit the blood stream at a particular secondary site (often in the lung, liver or bone). The tumor cells must adhere to particular molecules on the surface of the endothelial cells that line the inner surface of the blood vessels and then migrate across the vessel wall and into the tissue in the new site. The process of exit from the blood vessel into the tissue in a new site is called extravasation.
- After arriving in the new site, tumor cells often migrate away from poorly oxygenated sites adjacent to small veins (venules) and take up residence in more richly oxygenated regions adjacent to small arteries (arterioles). The earliest metastases may appear as single cells or small colonies of cells that wrap around arterioles in the secondary site.
Based on the processes outlined above, it is clear that metastatic tumor cells must retain or increase their ability to migrate and to invade across vessel walls and into tissues. Many studies have reported that cultured metastatic tumor cells move more rapidly than their non-metastatic counterparts. Thus the process of tumor progression to the metastatic state will often be facilitated by mutations that lead to increased cell motility. Many of these will be mutations in proteins involved in the assembly or disassembly of actin filaments. Alternatively, there may be mutations in signaling molecules that transduce signals necessary for the stimulation of cell movement.
Many proteins that have been discovered in screens for regulators of tumor metastasis are also regulators of cell migration. In general, proteins that stimulate migration will stimulate metastasis; proteins that inhibit migration will inhibit metastasis. A chart showing the correlation between metastasis-stimulating proteins and migration stimulating proteins is shown below.
Summary of Functional Effects of Factors on Prostate Cancer Cell Motility and Metastasis Molecules
or Effect on
|Acid Binding Proteins||TB15||+||+|
|Tumor Suppressor Genes||Bcl-2||+||+|
One goal of our research is to identify molecules that influence metastatic potential by affecting cell motility. One such example is thymosin b15, a molecule we found to be upregulated in highly metastatic prostate cancer cells. Because b-thymosins are known to interact with actin, a critical component of cell migration, we tested whether thymosin b15 could influence tumor cell motility. When thymosin b15 levels were lowered in metastatic prostate cancer cells, we found that their motility rate was dramatically reduced. These cells also showed reduced metastatic capability. These experiments reinforce the notion that metastasis and cell motility are intimately related in malignancy. We are now developing thymosin b15 as a diagnostic and prognostic marker for human prostate cancer.