The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis

Abstract

Recent pre-clinical and clinical research has provided evidence that cancer progression is driven not only by a tumour's underlying genetic alterations and paracrine interactions within the tumour microenvironment, but also by complex systemic processes. We review these emerging paradigms of cancer pathophysiology and discuss how a clearer understanding of systemic regulation of cancer progression could guide development of new therapeutic modalities and efforts to prevent disease relapse following initial diagnosis and treatment.

Figure 1

Composition of local and systemic tumour environments. (a) Cell types that comprise tumour tissues and play a role in cancer pathogenesis are depicted, including cancer cells, normal host cells and tumour-derived and/or -entrained cells. Some of the cells that operate within the tumour microenvironment originate from distant sources, including bone marrow and spleen; these cells are represented in areas of overlap between the indicated tissues. Also represented are other normal tissue cells, circulating cells and cell-free particles that are known to be modulated in response to malignancy. Some groups of cells (for example, bone-marrow-derived cells) are illustrated as a collection of differently coloured objects to represent their heterogeneity. This illustration also serves as a key to Figs 2 and 3. (b) Some of the tumour-derived cytokines (green text and differently coloured small particles) and microvesicles that are known to play a necessary role in mobilizing tumour-supportive host cells from tissues at distant anatomical sites. In some cases, these host cells are rendered pro-tumorigenic even prior to their mobilization. In most cases, the precise mechanism of action of these tumour-derived cytokines is not completely understood. Ultimately, these tumour-driven systemic events facilitate the growth of the initiating tumour. Solid arrows indicate activation or translocation of cell types and molecules; dashed arrows represent secretion of molecules.

Figure 2

Mechanisms of systemic regulation of metastatic tumour cell extravasation and colonization. (a) ‘Pre-metastatic niches’ are thought to form as a consequence of tumour-derived systemic factors that alter the tissue parenchyma of organs at distant sites, for example by extracellular matrix remodelling and activating resident tissue fibroblasts, as well as mobilizing bone-marrow-derived cells that subsequently incorporate into the parenchyma of these tissues. These niches are thus amenable to recruitment and extravasation of circulating metastatic tumour cells. Importantly, some tumour models have also revealed inhibitory factors that accumulate at pre-metastatic sites. (b) Circulating factors and bone-marrow-derived cells can affect disseminated micrometastases that would otherwise remain indolent, thus promoting their subsequent colonization into macroscopic metastases. For example, some reports have demonstrated promotion of vascularization by recruitment of pro-angiogenic bone-marrow-derived cells and platelets. Conversely, primary-tumour-derived anti-angiogenic factors have been reported to inhibit outgrowth of distant metastases. Other reports have revealed molecular mechanisms by which metastatic colonization is promoted by bone-marrow-derived cells that directly promote tumourcell proliferation and/or activation of tissue fibroblasts. Processes that affect colonization are represented in blue text, pro-tumorigenic factorsare represented in green text, and tumour inhibitory factors are shown in red text. Solid arrows indicate activation or translocation of cell types and molecules and dashed arrows represent secretion of molecules. For labelling key of cell types, see Fig. 1a.

Figure 3

Tumour-driven pathophysiological processes underlying cancer progression. Tumour-mediated events are depicted in space and time in a counter-clockwise fashion beginning with the initiating tumour. Although this cascade of events is represented in a unified fashion, it is clear that tumours from different cancer types employ different systemic tumour-promoting mechanisms that thus far seem to be context- and tissue-specific. In some cases, initiating tumours secrete cytokines into the circulation that cause mobilization of haematopoietic cells from distant organs; these cells can then contribute to pre-metastatic niche formation and/or promote metastatic colonization. In other cases, initiating-tumour-derived cytokines seem to directly affect growth of metastatic colonies at distant anatomical sites. In yet other cases, initiating-tumour-derived cytokines can be carried by circulating microvesicles or platelets, which serve as transporters of these cytokines to distant tissues or metastatic sites. Processes are represented in blue text, pro-tumorigenic factors are represented in green text, and tumour inhibitory factors are shown in red text. Solid arrows indicate activation or translocation of cell types and molecules and dashed arrows represent secretion of molecules. For labelling key of cell types see Fig. 1a.