Cancer Stem Cells: The Architects of the Tumor Ecosystem

Abstract

Cancer stem cells (CSCs) proactively remodel their microenvironment to maintain a supportive niche. Viewed through the lens of an ecosystem, numerous tumor components have multi-directional interactions involving CSCs, supporting the complexity of tumors to maintain growth in a dynamic host. In this Perspective, we discuss how CSCs are active architects of their microenvironment and drive interactions with other tumor components, such as immune cells, cancer-associated fibroblasts and differentiated cells, blood vessels, and other extracellular cues to engineer a sustainable niche. We also highlight considerations for modeling this dynamic tumor ecology and discuss potential therapeutic strategies for targeting these multifaceted interactions.

Figure 1.. Intratumoral crosstalk drives tumor microenvironmental heterogeneity.

Increasing inter-niche interactions sustain and grow the tumor microenvironment, creating an increasingly complex ecosystem that harbors the features of a high-grade tumor.

Figure 2.. CSCs engage in reciprocal signaling with each tumor niche that sustains the CSC population and promotes niche development.

Through a wide variety of niche-specific signaling mechanisms, CSCs promote immunosuppression, migration, therapeutic resistance, and EMT, while receiving supportive cues from each microenvironment that maintain stem-like features, such as self-renewal, migration and differentiation. Examples of mutually supportive CSC-niche interactions are detailed for each of the four described niches, including the hypoxic niche (blue), the immune niche (yellow), the perivascular niche (red), and the infiltrating region (green). CSC, Cancer stem cell; EMT, Epithelial-mesenchymal transition; Shh, Sonic hedgehog.

Figure 3.. Effective therapeutic strategies should target CSC-niche interactions.

Robustness is a critical component of a tumor modelled as a self-sustaining ecosystem. Thus, disruption of the intratumoral interactions driving that resilience will be crucial for effective treatment. For example, angiogenesis inhibitors may inhibit VEGF signaling (e.g. bevacizumab) or CSC-derived pericytes (e.g. via BMX inhibition). Checkpoint inhibitors such as PD-L1 or PD-1 antagonists (e.g. nivolumab, atezolizumab) have been used to target the bulk tumor of many solid cancers, but CSC-specific strategies may require the characterization and targeting of additional immunosuppressive or checkpoint mechanisms. Cytokine signaling, for example production of interleukin-6 by endothelial cells, or interleukin-4 by CSCs, promotes CSC maintenance and immunosuppression, respectively. Perivascular CSC-specific molecules, such as CD109 in glioblastoma CSCs, can be utilized in combination with strategies such as HIF inhibitors to target CSCs across multiples niches. CSC, Cancer stem cell.