Hypoxia-induced cancer cell reprogramming: a review on how cancer stem cells arise

Abstract

Cancer stem cells are a subset of cells within the tumor that possess the ability to self-renew as well as differentiate into different cancer cell lineages. The exact mechanisms by which cancer stem cells arise is still not completely understood. However, current research suggests that cancer stem cells may originate from normal stem cells that have undergone genetic mutations or epigenetic changes. A more recent discovery is the dedifferentiation of cancer cells to stem-like cells. These stem-like cells have been found to express and even upregulate induced pluripotent stem cell markers known as Yamanaka factors. Here we discuss developments in how cancer stem cells arise and consider how environmental factors, such as hypoxia, plays a key role in promoting the progression of cancer stem cells and metastasis. Understanding the mechanisms that give rise to these cells could have important implications for the development of new strategies in cancer treatments and therapies.

Keywords: Yamanaka factors; cancer stem cells; hypoxia; metastasis; reprogramming.

Figure 1

Schematics of different theories of CSC origin. (A) The stem cell theory of cancer postulates that cancer can arise from tissue stem cells and that CSC and/or cancer cells can give rise to normal, differentiated cells through transited amplifying cells. (B) In contrast, the somatic cell theory suggests that dormant stem cells become cancerous cells as a result of a mutation. (C) The cell reversal theory refers to a carcinogenic event that initiates cell de-differentiation to different epigenetic states that can develop into CSCs. (D) The stem cell misplacement theory alludes to basement membrane damage causing the misplacement of resident stem cells into the stoma leading to tumor formation and invasion. Created with BioRender.com.

Figure 2

Interaction of HIF factors and stemness generation through pluripotent stem cells markers. Hypoxia is a known hallmark of solid tumors and occurs when cells are deprived of oxygen. This causes the cells to switch to alternative metabolic pathways that allow them to survive and continue to grow. As a result, adaptations to hypoxia can lead to changes in the way tumor cells behave, making them more aggressive and resistant to chemotherapy and radiation. Given that tumors have a high metabolic demand and often outgrow their blood supply, HIFs are activated to regulate the expression of numerous genes that promote cell survival, proliferation, angiogenesis, and resistance to therapy. HIF-1α and HIF-2α have been linked to promoting CSCs stemness and phenotype through the upregulation of epigenetic regulators including SOX2, NANOG, OCT4, KLF4, and c-Myc. Created with BioRender.com.

Figure 3

Key features of Yamanaka transcription factors in cancer stem cells and tumor progression in hypoxic conditions. Hypoxia-induced expression of Yamanaka transcription factors is associated with CSC reprogramming, CSC maintenance, and tumor progression. SOX2, NANOG, OCT4A, KLF4, and c-MYC are all linked to pluripotency, CSC renewal, angiogenesis, EMT, and metastasis. While KLF4 has been shown to play a role in CSC reprogramming, its mechanism and regulation in the reprogramming of CSCs is not fully understood. Created with BioRender.com.

Figure 4

Different vascular structures seen in the tumor environment. Healthy tissue consists of normal vascularization, ECM, and tight junctions. As the solid tumor progresses, rapid tumor growth increases hypoxic niches and leads to abnormal angiogenesis. Abnormal vascular formation is also seen, allowing for metastasis through enhanced EMT. Hypoxia is known to increase HIF factors. As the hypoxic tumor environment progresses, HIF-2α expression rises and further promotes stemness in the hypoxic environment. Cancer stem cells have been positively correlated with vascular mimicry, in which ECM remodeling occurs along with epithelial-endothelial transitioning to create new vasculature into the hypoxic environment. Created with BioRender.com.