Cellular plasticity, cancer stem cells and metastasis

Abstract

Metastasis is a multistep process that implies genetic modifications and is strongly influenced by the interactions between host and tumor cells, and by tumor microenvironment. Before tumor cells colonize distant organs, they can prepare foreign soil by remotely coordinating a "premetastatic niche" from the primary tumor. The premetastatic niche provides an array of cells, cytokines, growth factors, and adhesion molecules to support metastatic cells on their arrival and to guide metastases to specific organs. Factors secreted by tumor cells, such as VEGF, LOX, IL-6, IL-10, and exosomes, participate in the premetastatic niche formation. Also extracellular matrix (ECM) molecules, namely periostin, tenascin and osteopontin can supply the necessary resources for successful metastatic colonization. One of the key underlying hypotheses of the cancer stem cell (CSC) model proposes that CSCs are the basis of metastases. CSCs in situ may transform to metastatic stem cells (MetSCs) by epithelial-mesenchymal transition (EMT) and subsequently disseminate and form metastatic colonies. Alternatively, MetSCs may derive from disseminated tumor cells that reacquire the competence to initiate tumor growth after a period of indolence. CSCs exhibit properties that are beneficial to metastasize and adapt in the foreign microenvironment, such as mesenchymal characteristics, increased capacity for DNA repair, resistance to apoptosis and to antitumor therapy. Circulating tumor cells (CTCs) are linked to tumor progression in a variety of solid tumors. CTCs are therefore assumed as precursors of distant metastasis. Potentially, a fraction of CTCs have CSC activity; stem-like CTCs may be a critical subset of CTCs with the capacity to form distant metastases. Many therapeutic strategies against CSCs strategies have been investigated. Among them, therapies directed at CSC niche and pre-metastatic niche are of particular interest. These therapies are aimed at targeting vasculature, extrinsic signals and tumor associated macrophages.