Cancer cell dissemination begins early, for example after escape from oncogene-induced senescence [43], and continues throughout tumor growth and progression. CTCs leaving the tumor no longer have contact with the supportive stromal microenvironment they are accustomed to, and the genetic and epigenetic changes they carry are usually insufficient to support their survival or growth as a fulminant metastasis. An appropriate stromal compartment therefore has to be re-established at secondary sites if DTCs are to survive and grow out as metastases. DTCs that do

not end up in an appropriate microenvironment (or which cannot initiate one) either selleck chemicals die or remain dormant, probably eventually regressing. If the microenvironment supports the survival of Selleckchem ABT 199 the DTCs, or is modified to support their survival, then the DTCs can continue to acquire genetic mutations and aberrations at secondary sites, and progress genetically in parallel to tumors cells in the primary tumor, as foreseen in the parallel

progression model. However, concurrent stromal progression also accompanies these genetic changes in the tumor cells at the secondary site, similar to the case in the primary tumor (Fig. 1). Stromal progression also takes place at secondary sites to form microenvironments that support outgrowth of metastases. Such microenvironments may be initiated and developed in a number of conceivable ways: (i) DTCs may settle in pre-existing microenvironments Astemizole that provide stromal components they need. These may be normal stem cell niches, for example, or pre-metastatic niches induced by the primary tumor. (ii) Factors produced by the DTCs themselves may act on the surrounding stroma and initiate or contribute to the

stromal progression that ultimately supports secondary tumor growth. Thus genetic changes in tumor cells can promote stromal progression. (iii) Tumor–stroma interactions in the primary tumor produce increasing quantities of soluble factors as the tumors grow, such as growth factors, cytokines and chemokines. These begin to accumulate systemically and ultimately induce the formation of metastatic niches as described above, either pre-metastatically or after the dissemination of DTCs. Hence the size of the primary tumor correlates with the incidence of metastasis, as size is proportionate to the amount of factors produced. (iv) Once a primary tumor has been removed, parallel genetic progression in the DTCs and/or associated stromal progression may eventually lead to outgrowth of metastases. In addition, other pathological events such as tissue trauma or chronic inflammation may release sufficient systemic levels of growth factors and cytokines that induce metastatic niche formation such that metastatic niche formation is kick-started and/or stromal progression is supported.