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Organ Targeting: Anatomic vs Seed & Soil Models

The Anatomic Model

In the anatomic model of metastsis, secondary tumors occur in the organs which they encounter first during their dissemination from the primary tumor. This scenario appears to occur in regional metastases, where tumor cells gain access to nearby tissue or lymph nodes through the blood or lymphatic circulation. For example, liver metastasis is a major occurrence in patients with colorectal cancer. In this case, the capillary bed of the liver is the first encountered by the tumor cells after leaving the colon, and the liver seems to provide a suitable environment for the growth of these secondary tumors. However, metastasis to distant organs occurs through a different mechanism (see next section).

The Seed and Soil Hypothesis

Early cancer researchers noticed a propensity for certain cancers to metastasize to the same organ.  In 1889 Stephen Paget observed that patients with breast cancer often developed secondary tumors in the liver.  He considered it unlikely that this occurrence was due primarily to accessibility of the liver by the blood supply, as other organs receiving equivalent blood supply rarely developed metastases.  He instead developed the "Seed and Soil" hypothesis, in which certain tumor cells (the seeds) can only successfully colonize selective organs (the soil) that have suitable growth environments .

The current view of the Seed and Soil Hypothesis consists of three important concepts.

1. Primary tumors and their metastases consist of genetically diverse tumor and host cells (for more on the role of the host cells in cancer, see the section on Tumor Microenvironment).
2. Metastasis selects for cells that can succeed in all phases of the metastatic process.  In essence, a successful metastatic cell must be a decathalete: good in all the events, and not just one or two.
3. Metastases generally develop in a site specific way.  Because the microenvironments (the soil) of each organ is different, individual cancer cells may be able to colonize one specific organ.

At the heart of the Seed and Soil hypothesis is the idea that successful metastasis depends on the interaction of the metastasizing tumor cells with the cells of the target organ (the stroma, or tumor microenvironment).  Not only must tumor cells must be able to produce factors that alter the stromal cells in such a way as to better serve the survival and growth of the tumor, but the environment in which the cancer cell finds itself must be capable of responding to those signals.  If the cancer cell finds itself in an inhospitable soil (i.e. it cannot subvert the stroma to serve its needs), successful metastsis will be impossible.

Recent studies examining the profile of genes expressed in tumors that metastasis to specific organs have identified specific genetic signatures of these tumors.  For example, genes that mediate the metastasis of breast cancer to bone are different than those that mediate metastasis to the lung.  In essence, different sets of genes allow tumor cells to specifically interact with the stromal cells of the target organ. These findings may lead to therapeutic strategies to target the metastatic properties of tumors. 

A closer look at the formation and colonization of the pre-metastatic niche.