The metastatic niche and stromal progression

Abstract

The tumor stroma is comprised of extracellular matrix, non-malignant cells, and the signaling molecules they produce. It is an integral and vital component of primary tumors that together with the underlying genetic defects in the tumor cells determines the growth characteristics, morphology, and invasiveness of the tumor. In parallel to continuing genetic changes in the tumor cells themselves, the tumor stroma progressively evolves during primary tumor development. Cancer cells that disseminate from primary tumors are dependent on this stromal microenvironment, and therefore the microenvironment they encounter at secondary sites determines their fate. For those cells that survive at these sites, stromal progression can serve to re-establish a supportive tumor stroma, fostering the outgrowth of the cells as metastases. Formation of a metastatic niche that supports the survival and growth of disseminated tumor cells is a key feature of this stromal progression. The endogenous organ microenvironment can provide components of the metastatic niche. In addition, microenvironmental changes in organs prior to receipt of disseminated tumor cells can be induced by factors secreted systemically by primary tumors, causing the formation of pre-metastatic niches. Further maturation of metastatic niches can be responsible for the re-activation of dormant disseminated tumor cells many years after removal of the primary tumor. The concept of the metastatic niche and stromal progression has profound consequences for our understanding of metastatic disease, and promises to open up new strategies for the diagnosis, prognostic evaluation, and therapy of cancer.

Fig. 1

Diagram showing the relationship between CTCs, DTCs, and the metastatic niche. The current concept of the metastatic niche and important components within it are illustrated

Fig. 2

Diagram illustrating our current understanding of stromal progression at sites of metastasis formation. Intrinsic properties of CTCs determine their ability to extravasate into distant organs. In these organs, CTCs encounter either the endogenous niche environment of the organ concerned or a remodeled pre-metastatic niche microenvironment that has been induced by the primary tumor. This pre-metastatic remodeling may be sufficient by itself to produce a metastatic niche that is competent to support metastasis. Alternatively, additional microenvironmental remodeling may be required once a DTC has become established in situ to convert either the endogenous organ microenvironment or a partially remodeled pre-metastatic niche into to a fully competent outgrowth-supporting metastatic niche. A number of factors are listed that may be required for the remodeling that results in metastatic niche formation. Various fates are possible for DTCs. These are determined by the intrinsic properties of the DTC as well as by the particular microenvironment that the DTC finds itself in