The bed and the bugs: Interactions between the tumor microenvironment and cancer stem cells

Abstract

Tumors have been increasingly recognized as organs with a complexity that approaches, and may even exceed, that of healthy tissues. When viewed from this perspective, the biology of a tumor can be understood only by studying tumor cell heterogeneity and the microenvironment that is constructed during the course of tumorigenesis and malignant progression. Recent work has revealed the existence of cancer stem cells, the "bugs", with the capacity for self-renewal and tumor propagation. In addition, it is now recognized that the tumor microenvironment, the "bed", plays a critical role in supporting cancer stem cells and also may promote neoplasia and malignant progression. The interdependence of the cell-intrinsic features of cancer, including the cancer stem cell "bugs" and the tumor microenvironment "bed", is only beginning to be understood. In this review, we highlight the rapidly evolving concepts about the interactions between tumor stem cells and their microenvironment, the insights gained from studying their normal tissue counterparts, and the questions and controversies surrounding this area of research, with an emphasis on breast and lung cancer. Finally, we address evidence supporting the notion that eliminating the bed as well as the bugs should lead to more effective and personalized cancer treatments that improve patient outcome.

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

“…Therefore, in the TME, CAFs have been an on-going challenge due to the lack of CAF-specific markers and the vast heterogeneity of these cells. Accumulating evidence support that CAFs facilitate tumor initiation, growth and progression (Calvo and Sahai, 2011; Castaño et al, 2012; Quail and Joyce, 2013) and tumor invasion and metastasis by mediating tumor-enhancing inflammation (Erez et al, 2010). The data suggests that CAFs strongly promote the development of an aggressive cancer cell phenotype (Donnarumma et al, 2017).…”

Breast Cancer Intra-Tumor Heterogeneity: One Tumor, Different Entities

“…Stromal cells also secrete factors that induce EMT on epithelial cancer cells 99 . Likewise, tumors with hypoxic regions due to poor vascularization have undifferentiated stem-like tumor cells that survive under the action of hypoxia-inducible factors (HIF) transcription factors family, apparently by inhibiting cell differentiation and maintaining stem-like phenotype 100 .…”

Aberrant Splicing in Cancer: Mediators of Malignant Progression through an Imperfect Splice Program Shift

“…TGF-β, the gold standard, has been used to efficiently induce EMT [4,22,23,24]. However, several stimuli can trigger EMT [25,26,27,28,29]. It is important to highlight that several of these stimuli, mainly cytokines and growth factors, activate signaling pathways and transcription factors as effectors, which can further modulate the activity and expression of splicing factors [30].…”