The Evolving Portrait of Cancer Metastasis

Abstract

The phenomenon of cancer metastasis remains poorly understood. We discuss here various conceptual frameworks that attempt to rationalize the mechanisms by which tumors acquire metastatic ability. Portrayal of cancer as a somatic Darwinian process occurring within a tissue fails to fully explain the phenomenon of metastatic competence. The biology of pre-neoplastic cells also complicates this picture, since the phenotypes of normal cellular precursors are clearly relevant to metastatic behavior following transformation. Recent experimental results help to shed light on these and other considerations regarding the molecular mechanisms of malignant progression."colonization"). The complexity of this process has caused many to assume that numerous genetic lesions are required within individual cancer cells in order to enable them to complete this cascade. If this were so, the probability of any one of these mutations occurring is small, and, therefore, the likelihood of all requisite lesions occurring together within a single cell is negligibly small.Alternative scenarios offer resolutions of this conceptual quandary ( Fig. 1):1. Some traits that are advantageous to cancer cells within the primary tumor microenvironment may also contribute to metastatic competence. Resistance to apoptosis, for example, may be dually advantageous for cancer cells-for survival within the primary tumor microenvironment and also for survival in the circulation or at secondary organ sites (prior to colonization), thereby contributing to metastatic competence.2. Selective pressure within the primary tumor microenvironment for phenotype X may result in the clonal expansion of cancer cells harboring a genetic lesion that also happens to confer a second phenotype Y, the latter contributing to metastatic competence. Thus, cancer cells may acquire a particular phenotype that is advantageous within the primary tumor microenvironment through one of several possible genetic lesions, some of which fortuitously confer additional phenotypes that facilitate cancer cell metastasis.The possibilities delineated above describe how metastatic phenotypes may hitchhike along with phenotypes that are beneficial within the primary tumor microenvironment, resulting in the clonal expansion of metastasis-competent cells within the primary tumor. These scenarios may help to resolve the conceptual difficulties inherent in extending an evolutionary model of tumor progression to include metastasis. However, recent unanticipated observations with tumor specimens obtained from cancer patients call into question the applicability of the Darwinian framework to the acquisition of metastatic competence. In particular, classifiers based on mRNA expression profile arrays have demonstrated that the transcriptional state of relatively early-stage primary tumors is predictive of the ultimate clinical prognosis of patients van't Veer et al. 2002;Huang et al. 2003;Ramaswamy et al. 2003; Glinsky et al. 2004a,b;Wang et al. 2005). This surprising finding appears to be fundamental...

A putative role for microRNA-205 in mammary epithelial cell progenitors

“…These changes in Sca-1 + colony size are probably attributed to the increase in proliferation that was observed in the miR-205-overexpressing cells. (Mattie et al, 2006); f BC compared with normal breast (Volinia et al, 2006); within a genomically amplified region in BC (Blenkiron et al, 2007) (Mattie et al, 2006); F BC compared with normal breast (Volinia et al, 2006); within a genomically amplified region in BC (Blenkiron et al, 2007) (Mattie et al, 2006); F BC compared with normal breast (Volinia et al, 2006); within a genomically amplified region in BC (Blenkiron et al, 2007) (Mattie et al, 2006); located near the HOXC cluster, a potential site for disregulation in cancer (Calin et al, 2004); within a genomically amplified region in BC (Blenkiron et al, 2007) miR-34a -2.82 F PR + BC (Mattie et al, 2006); within a deleted region associated with BC (Calin et al, 2004;Gupta et al, 2005) Rajewsky and Socci, 2004), but often these algorithms will predict different targets for the same miRNA. PTEN was identified as a predicted target of miR-205 by the miRanda algorithm at the miRNA Viewer website (http://cbio.mskcc.org/mirnaviewer/).…”

The basics of epithelial-mesenchymal transition

“…The actual implementation by these cells of their EMT program depends on a series of intracellular signaling networks involving, among other signaltransducing proteins, ERK, MAPK, PI3K, Akt, Smads, RhoB, β-catenin, lymphoid enhancer binding factor (LEF), Ras, and c-Fos as well as cell surface proteins such as β4 integrins, α5β1 integrin, and αVβ6 integrin (80). Activation of EMT programs is also facilitated by the disruption of cell-cell adherens junctions and the cell-ECM adhesions mediated by integrins (67,75,(81)(82)(83)(84)(85)(86).…”

Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival

“…carcinoma | receptor tyrosine kinase | breast cancer M etastasis to distant sites is the most common cause of death from carcinomas (1). Malignant cells discard epithelial restraints and acquire invasive motility that facilitates dissemination to permissive niches (2).…”