Metastasis: A Therapeutic Target for Cancer

Patricia S Steeg; Dan Theodorescu


Nat Clin Pract Oncol. 2008;5(4):206-219. 

In This Article

Primary Tumors and Metastases: Separate and Unequal

Figure 1 illustrates trends for colorectal carcinoma, for which the resection of liver metastases is occasionally performed. Supplementary Table 1 shows a more complete listing of studies regarding matched primary and metastatic lesions, in addition to a meta-analysis of multiple comparative genomic hybridization (CGH) studies. The expression of genes from matched sets of primary tumors and metastases co-clustered in profiling experiments, indicating their overall similarity. The data do not, however, indicate their complete identity. Studies have identified distinct expression trends at the RNA or protein levels in primary tumors and metastases, including genes that control metastasis (MTA1, N-Wasp, NCAML1), extracellular matrix function (fibronectin, collagens), microtubule dynamics (stathmin), transcription (Snail), drug-processing enzymes (DPD, TS) and kinases (Yes1).[3,4,5,6,7,8,9] Differences occurred both homogeneously and heterogeneously in the matched sets examined.[10]

Molecular distinctions between primary colorectal carcinomas and their liver metastases. While primary tumors and metastases are identical in many respects, differences exist. Two types of comparisons are listed: molecular analyses of matched primary tumors and resected liver metastases (mutation, RNA and immunohistochemistry data), and a meta-analysis of CGH data generated from both matched and unmatched samples. References are listed in Supplementary Table 1. Abbreviations: CGH, comparative genomic hybridization; IHC, immunohistochemistry.

The quantification issues related to comparisons of matched primary tumors and metastases assessed using CGH, fluorescence in situ hybridization (FISH), and mutation analyses are more straightforward. A meta-analysis showed that the development of liver metastases in patients with colorectal cancer was accompanied by a series of chromosomal deletions and gains in at least 15% of the tumor specimens; this finding raises the issue of heterogeneity.[11] Lung metastases showed more genomic alterations than liver metastases. Analyses of primary tumor-metastasis colorectal carcinoma sets showed that the Ki-ras mutational status was discordant in 30%,[12] and FISH analysis demonstrated that 27% of lung cancer primary tumors and metastases were discordant in EGFR copy number.

The variability between metastases within a single patient and between patients could be answered by rapid autopsy.[13] In summary, the expression profiles produced for primary tumors and matched metastases are generally concordant; however, differences in expression do exist, and prompt two further questions: First, what genes or pathways are mechanistically involved in distinguishing primary tumors and metastases? Second, do these distinctions make a difference -- that is, do primary tumors and metastases respond differently to therapeutics?

Many of the molecular pathways that promote tumorigenesis also promote metastasis and are important in the treatment of both aspects of cancer progression. Some genes exert effects only on metastatic capability, and many of these are relevant to metastatic colonization. Metastasis suppressor genes represent prime examples of metastasis-specific regulation.[14] Most metastasis suppressors were identified on the basis of their reduced expression in highly metastatic versus poorly metastatic cell lines or tissues. Transfection of a metastasis suppressor gene into a metastatic cell line resulted in decreased metastatic capability with no significant effect on primary tumor size. Most metastasis suppressors inhibit late steps in the metastatic cascade: tumor cells expressing the Kiss1 and MKK4 metastasis suppressors arrive in the lungs at frequencies comparable to control transfectants but fail to form large metastases.[15,16] Specific signaling pathways affected by metastasis suppressors in colonization include Nm23 modulation of the Erk pathway, Brms1 alteration of phosphoinositide signaling, and Mkk4 activation of Jnk and p38 stress pathways.[14] Some genes promote metastasis without affecting tumorigenesis,[17,18] while others affect the host interaction with the metastasizing tumor cell, such as Src-regulated vascular permeability.[19]

Primary tumors and metastases exhibit minor but important differences; however, this is a merely academic argument if they always respond similarly to environmental conditions or drugs. Table 1 summarizes results generated in model systems, in which various treatments have produced disparate effects on primary tumor growth and metastases. These studies include diverse cancer histologies and compounds that target multiple pathways. In summary, primary tumors and metastases can differ in expression profiles. They can use distinct molecular pathways and drugs can differentially affect their development. Given these possibilities, we advocate the incorporation of metastasis models in drug-development studies.


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