Cancer and Microenvironment Plasticity: Double-Edged Swords in Metastasis

Abstract

Cancer initiates at one site (primary tumor) and, in most cases, spreads to other distant organs (metastasis). During the multistep process of metastasis, primary tumor cells acquire cellular and phenotypic plasticity to survive and thrive in different environments. Moreover, cancer cells also utilize and educate microenvironmental components by reshaping them into accomplices of metastasis. Recent studies have identified a plethora of new molecular and cellular modulators of metastasis that have dynamic or even opposite roles, dominating the phenotypic plasticity of both tumoral and microenvironmental components. In this review we discuss their bipotential functions and the possible underpinning mechanisms, as well as their implications for targeted cancer therapy.

Keywords: bipotential regulators; heterogeneity; metastasis; microenvironment; plasticity.

Figure 1.. WNT as a bi-potential modulator of metastasis.

WNT plays stage-dependent contrary roles in both bone (A) and lung (B) metastasis. In osteolytic bone metastasis (of breast cancer, for example) and the early stage of osteoblastic bone metastasis (of prostate cancer, for example), tumor-derived transient high level of WNT inhibitor DKK1 suppresses osteoblast differentiation to osteocytes but enhances osteoclast differentiation. Bone matrix degradation ensues that releases growth factors to nurse disseminated tumor cells (DTCs) (A, left panel). In the late stage of osteoblastic bone metastasis, DKK1 level is tuned down to unleash osteoblast differentiation, leading to full-blown osteoblastic colonization (A, right panel). Similarly, in the early stage of lung metastasis (B, left panel), the transient high level of DKK1 maintains the quiescence of DTCs to allow evasion from immune surveillance by natural killer (NK) cells. Later, DKK1 level is tuned down and the activation of WNT signaling pathway supports outgrowth of lung metastasis (B, right panel).

Figure 2.. Cellular components of TME that play opposite roles in metastasis.

During metastatic growth, different tumor microenvironment (TME) cells possess seemingly contradictory regulatory effects on tumor cell dissemination and metastatic colonization. These cells include, but are not limited to, endothelial cells (ECs), fibroblasts, neutrophils and macrophages. The pro- and anti- metastasis functions of each are listed below the respective cell type.