Formation of benign tumors by stem cell deregulation

Abstract

Within living organisms, stem cells respond to various cues, including to niche signals and growth factors. Niche signals originate from the stem cell’s microenvironment and promote the undifferentiated state by preventing differentiation, allowing for stem cell self-renewal. On the other hand, growth factors promote stem cell growth and proliferation, while their sources comprise of a systemic input reflecting the animal’s nutritional and metabolic status, and a localized, homeostatic feedback signal from the tissue that the stem cells serve. That homeostatic signal prevents unnecessary stem cell proliferation when the corresponding differentiated tissues already have optimal cell contents. Here, we recapitulate progresses made in our understanding of in vivo stem cell regulation, largely using simple models, and draw the conclusion that 2 types of stem cell deregulations can provoke the formation of benign tumors. Namely, constitutive niche signaling promotes the formation of undifferentiated “stem cell” tumors, while defective homeostatic signaling leads to the formation of differentiated tumors. Finally, we provide evidence that these general principles may be conserved in mammals and as such, may underlie benign tumor formation in humans, while benign tumors can evolve into cancer.

Understanding cancer from an evolutionary perspective: high-risk reprogramming of genome-damaged stem cells

“…Genome changes and oncogenic transformations are still pending. Nonetheless, Valet and Narbonne [43] consider 2022 benign tumor cells as dysfunctional noncancerous cell types capable of completing oncogenic transformation and form malign tumors. Benign tumors result from stem cell deregulation [44,45]; however, the dysregulation occurs at different stages of stem cell development and under the influence of different stimuli (niche stimuli) and growth factors [46][47][48][49][50][51].…”

“…Normally, the niche environment maintains the undifferentiated, undamaged phenotype by preventing differentiation, but when Notch signals were blocked, all cells in the niche were rapidly stimulated to differentiate [53][54][55]. According to Valet and Narbonne [43], two types of niche signals lead to stem cell deregulation and benign tumor formation: (i) early constitutive niche signals that lead to undifferentiated tumors and (ii) later defective homeostatic signals that lead to differentiated tumors. The authors believe that "undifferentiated benign tumors can arise when a mutation constitutively activates niche signaling," and show that "mutations in genes encoding several highly conserved proteins prevent homeostatic germ stem cell (GSC) regulation in Caenorhabditis elegans.…”

“…According to Valet and Narbone [43], benign tumors "acquire changes that disrupt homeostatic stem cell regulation by their differentiated progeny and prevent proper stem cell differentiation, respectively stem cell quiescence". The authors propose that mutations affecting terminal differentiation promote the development of benign or abnormally differentiated tumors.…”