Recasting the Cancer Stem Cell Hypothesis: Unification Using a Continuum Model of Microenvironmental Forces

Abstract

Purpose of review: Here, we identify shortcomings of standard compartment-based mathematical models of cancer stem-cells, and propose a continuous formalism which includes the tumor microenvironment. Recent findings: Stem-cell models of tumor growth have provided explanations for various phenomena in oncology including, metastasis, drug-and radio-resistance, and functional heterogeneity in the face of genetic homogeneity. While some of the newer models allow for plasticity, or de-differentiation, there is no consensus on the mechanisms driving this. Recent experimental evidence suggests that tumor microenvironment factors like hypoxia, acidosis and nutrient deprivation have causative roles. Summary: To settle the dissonance between the mounting experimental evidence surrounding the effects of the microenvironment on tumor stemness, We propose a continuous mathematical model where we model microenvironmental perturbations like forces, which then shape the distribution of stemness within the tumor. We propose methods by which to systematically measure and charaterize these forces, and show results of a simple experiment which support our claims.

Non-autonomous regulation of germline stem cell proliferation by somatic MPK-1/MAPK activity inC. elegans

“…ERK/MAPK is upregulated in many human cancers [1][2][3][4] , though its primary role in embryonic stem cells centers on differentiation [7][8][9][10] . Importantly, tumours are heterogeneous and only cancer stem cells generate a new tumour upon transplantation 62,63 . The bulk of the tumour therefore likely consists of the progeny of cancer stem cells, which are in various states of differentiation.…”

Discovering New Progenitor Cell Populations through Lineage Tracing and In Vivo Imaging

“…Another intensively debated subject in cancer research is the existence of "cancer stem cells" (CSCs) ( Fig. 5B; reviewed by Kreso and Dick 2014;Batlle and Clevers 2017;Scott et al 2019). Akin to the stem cells that constitute a fraction of different adult organs, tumors have also been suggested to possess CSCs that can self-renew and generate cells for tumor growth and malignancy (Beck and Blanpain 2013).…”

“…The identification of CSCs had inspired newer strategies of cancer therapies aiming at their elimination. Nevertheless, growing evidences indicate that both CSC and non-CSC populations within a tumor might be plastic, and their tumorigenic potential may be altered by the tumor microenvironment (for reviews, see Batlle and Clevers 2017;Scott et al 2019). In support of this idea, it has been shown that in intestinal tumors, epithelial non-stem cells can dedifferentiate into tumor-initiating cells (Schwitalla et al 2013).…”

Inferring Tumor Proliferative Organization from Phylogenetic Tree Measures in a Computational Model

“…The CSCH provides a conceptual framework by which to understand many different aspects of cancer progression, including: the occurrence of functional heterogeneity despite genetically identical states [2][3][4] ; resistance to chemotherapy 5,6 and radiotherapy [7][8][9] ; recurrence 10 ; and metastasis 11 . Despite its popularity, the CSCH has been the subject of continual debate and modification in order to maintain compatibility with experimental observations [12][13][14] .…”