Metastasis: a therapeutic target for cancer

Abstract

Metastasis remains the major driver of mortality in patients with cancer. Our growing body of knowledge regarding this process provides the basis for the development of molecularly targeted therapeutics aimed at the tumor cell or its interaction with the host microenvironment. Here we discuss the similarity and differences between primary tumors and metastases, pathways controlling the colonization of a distant organ, and incorporation of antimetastatic therapies into clinical testing.

Figure 1

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.

Figure 2

Metastatic colonization. Metastatic colonization represents a prime window of opportunity to interrupt the metastatic process. Growth in a distant site has similarities and differences to that in the primary tumor site. Steps in metastatic colonization are listed on the left, with potential breaks for dormancy shown. Potential therapeutic strategies are listed to the right.

Figure 3

The bone metastasis ‘vicious’ cycle with recent updates. Metastatic tumor cells interact with the bone microenvironment to facilitate osteolytic colonization. Tumor cells secrete PTHrP, which stimulates osteoblasts (bone-forming cells) to produce both a membrane-bound RANKL and OPG, a soluble decoy receptor for RANKL. It is the ratio of RANKL to OPG that determines osteoclast (bone-degrading cell) activation, through its receptor for RANKL. Activated osteoclasts degrade the bone matrix, releasing into the local microenvironment embedded growth factors including TGF-β. TGF-β stimulates tumor-cell PTHrP production, renewing the cycle. Recently, RANKL was reported to stimulate tumor cells as well as osteoclasts, inducing motility that could spread bone colonization. Tumor cells also produce GM-CSF, a hematopoietic growth factor used in cancer therapy. GM-CSF, in turn, stimulated bone marrow cells to produce more osteoclasts, amplifying the cycle. Abbreviations: GM-CSF, granulocyte macrophage-colony stimulating factor; OBL, osteoblast-like cells; OCL, osteoclast-like cells; OPG, osteoprotegerin; PTHrP, parathyroid-hormone-related protein; RANKL, receptor activator of NF-κB ligand; TGF-β, transforming growth factor-β.

Figure 4

An overwhelming number of potential rational combinations of drugs are available for metastatic colonization: angiogenesis as an example. Inhibitors of VEGF and its receptor (VEGFR) have been brought to clinical testing. Potential rational combinations are shown by lines, including aspects of tumor cell biology, the microenvironment and traditional cytotoxics.,,, Abbreviations: EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; RTKs, receptor tyrosine kinases; TKIs, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor.