Metastasis: A Therapeutic Target for Cancer

Patricia S Steeg; Dan Theodorescu

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

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]

(Enlarge Image)

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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Summary and Introduction
Primary Tumors and Metastases: Separate and Unequal
Metastatic Colonization
Clinical Targeting of Metastatic Colonization
Conclusions
References
Sidebar: Key Points
Sidebar: Potential Elements That Support the Conduct of Clinical Trials of Drugs Targeting Metastatic Colonization in the Adjuvant Setting

In Model Systems, Therapeutics and Environmental Conditions Can Differentially Affect Primary Tumors and Metastases
Histology	Findings	Reference
Breast	Systemic administration of a TGF-ßRI-I inhibitor reduced the number of lung metastases and the incidence and burden of bone metastases with no effect on the orthotopic primary tumor	Bandyopadhyay et al. (2006)^[95]
	Integrin-based peptidomimetics reduced lung metastasis by 44-68%, with no effect on primary tumor growth and only a minor difference in the number of circulating tumor cells	Shannon et al. (2004)^[51]
	The topoisomerase II inhibitor salvicine reduced lung metastasis by 33-68%, with no diminution of primary tumor growth, via a RhoC pathway	Lang et al. (2005)^[96]
Osteosarcoma	Parthenolide, a NF-κB directed agent, inhibited lung metastasis fourfold in a prevention model with no significant effect on the growth of primary tumors. A similar trend was reported for mutant IκBα expression	Kishida et al. (2007)^[50]
Prostate	Norepinephrine increased, and propranolol decreased the lumbar lymph-node metastases of PC-3 cancer cells; growth of the primary tumor was not affected	Palm et al. (2006)^[97]
Prostate and melanoma	PC3M prostate and B16 melanoma cells were treated ex vivo with C90, a Grb-2 inhibitor, and injected. The compound inhibited lung metastasis by 50%, with no significant effect on primary tumor size	Giubellino et al. (2007^[98]
Cervical	Acute hypoxia significantly decreased primary tumor size but increased the number of positive lymph nodes and the size of the lesions	Cairns and Hill (2004)^[99]
Pancreatic	Cyclopamine reduced the incidence of distant metastases to the spleen, liver, lymph nodes and peritoneum, with no significant effect on primary tumor volume	Feldmann et al. (2007)^[9]
Lung	RPI-1, a c-Met inhibitor, did not inhibit subcutaneous tumors produced by H460 lung cancer cells at 100 mg/kg, but reduced metastases by 57%	Cassinelli et al. (2006)^[100]

Sidebar: Key Points

Most information on human cancer is obtained from analysis of primary tumors and yet this knowledge is applied to the treatment of metastases
There is mounting genetic evidence that the molecular wiring of a metastatic lesion has both elements in common with and elements that are distinct from those of primary tumors
Targeting the last step in the metastatic process, outgrowth at a distant site, termed 'metastatic colonization', holds great therapeutic promise
Blockade of metastatic colonization can be accomplished by targeting the metastatic cancer cell or the host cell, or by interrupting reciprocal interactions between tumor cells and the foreign microenvironment; therapeutic efforts can target metastatic colonization at all sites or interactions specific to a particular organ (bone, for instance)
Novel clinical trial designs with short-term molecular and pharmacodynamic end points should be considered
Approaches to inhibit metastatic colonization may show their best efficacy in the adjuvant setting

Sidebar: Potential Elements That Support the Conduct of Clinical Trials of Drugs Targeting Metastatic Colonization in the Adjuvant Setting

The effect of a drug on metastatic colonization may be best measured in the adjuvant clinical setting. In the adjuvant setting, the drug should be administered to patients who are without detectable distant metastatic disease, but are at high risk for its development -- for instance, breast cancer patients with tumor cells in the axillary lymph nodes. Given the expense, large size and time required for adjuvant trials, what data should optimally be available? The following are suggested:

Did the compound impact the molecular target in multiple preclinical models? In the clinic?
Did the compound elicit stable disease (>6 months) or, less likely, objective clinical responses in the metastatic setting?
Is the drug active at all sites or is it site-specific?
Has an optimum rational combination been identified and tested clinically in the metastatic setting?
Have the patient selection criteria been optimally chosen for the molecular target or metastatic tissue?
What was the duration of treatment?
Are the end points adequately delineated?
Are validated biomarkers of response being used?

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