Determinants of metastatic competency in colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most common cancer types and represents a major therapeutic challenge. Although initial events in colorectal carcinogenesis are relatively well characterized and treatment for early-stage disease has significantly improved over the last decades, the mechanisms underlying metastasis - the main cause of death - remain poorly understood. Correspondingly, no effective therapy is currently available for advanced or metastatic disease. There is increasing evidence that colorectal cancer is hierarchically organized and sustained by cancer stem cells, in concert with various stromal cell types. Here, we review the interplay between cancer stem cells and their microenvironment in promoting metastasis and discuss recent insights relating to both patient prognosis and novel targeted treatment strategies. A better understanding of these topics may aid the prevention or reduction of metastatic burden.

Keywords: Heterogeneity; TGF-beta; cancer immunology; cancer stem cells; clonal diversity; combination therapy; dormancy; immunotherapy; stroma; tumour microenvironment.

Figure 1

Types of heterogeneity underlying the process of CRC metastasis. Schematic representation of a primary tumour with clonal diversity (represented by different colours), tumour microenvironment (different cell shapes) and cellular hierarchy: colorectal cancer stem cells (CRC‐SCs) are drawn with darker colours than non‐stem cells (non‐SCs). In addition, metastatic stem cells (Met‐SCs) are represented by thicker outlines. There are distinct steps (blue arrows) along the metastatic process, each with attrition rates: survival in the vasculature during migration, overcoming mechanisms of latency and managing to establish an overt metastatic colony. During these events, interactions with the microenvironment that promote survival, immune evasion, dormancy/proliferation and stemness are thought to determine outcome. Below: legends depict a basic scheme of cellular hierarchy and the wealth of stromal cell types.

Figure 2

Mechanisms and therapeutic opportunities in early dissemination. In the centre is a cancer stem cell (CRC‐SC) that is in the process of invasion (which might involve EMT or tumour budding) or vascular migration. Depicted are various recently described interactions with stromal cells: proteins expressed by stromal cells are depicted in black, processes in bold, activated pathways in red and relevant cellular markers are written in blue (drawn inside grey labels). Agents or inhibitors that target pathways or proteins are drawn in green. See the main text for more details.

Figure 3

Mechanisms and therapeutic opportunities in the metastatic setting. In the centre is a metastatic stem cell (Met‐SC) that is in the process of colonizing the liver. Depicted are various recently described interactions with stromal cells: proteins expressed by stromal cells are depicted in black, processes in bold, activated pathways in red and relevant cellular markers are written in blue (drawn inside grey labels). Agents, inhibitors or therapeutic strategies that target pathways or proteins are drawn in green. See the main text for more details.