Heterogeneity and Cancer initiation:
Cancer initiates within the habitat of the tissue and cancer cells grow in the space of host cells52. Lately, it has been recognized that cancer cells enter into a survival battle with the surrounding host cells during tumorigenesis, and can kill the host cells to make space for their growth52–57. Excitingly, in many cases, similar competitive interactions allow host cells to recognize the emerging cancer cells and extrude them out of the tissue58–64. An understanding on how cancer cells outcompete the surrounding host cells during cancer initiation may open doors to novel targeted therapies52. Studies in the past few years have demonstrated clonal competition and selection during tumorigenesis in both in-vitro 65–67 andin-vivo 52–57,66–77 model systems. In addition, signalling molecules playing mechanistic roles in cellular-competition during tumorigenesis have been described in several studies78–87. However, description of cell competition remains incomplete without factoring in the inherent cellular heterogeneity within the tissues. How does tissue heterogeneity affect selection of mutants during cancer initiation and progression? Do biochemical and physical heterogeneity within the tissues affect the competitive interactions within cancer cells and host cells? Slaughter’s concept of field cancerization88 suggest that biochemical heterogeneity caused by the genetic and epigenetic differences within the cells would play a crucial role in determining growth or suppression of cancer cells. To this end, a recent study demonstrate that genetic heterogeneity across the tissue plays an essential role in determining survival of early neoplasms in mouse esophageal tissue89. Another study in mice thyroid tissue shows that intrinsic properties of thyroid follicles determined fate of mutant cells. Follicular heterogeneity and thyroid tissue organization dictated the fate of BRAF mutant cells90with an increased propensity of BRAF mutants to develop tumor in the postnatal Thyroid.
Besides the genetic and mutational landscape of tissues, studies suggest that tumour initiation may also depend on the mechanical landscape of tissues. While mutant HRas-V12 cells are successfully extruded out from the epithelial monolayer cultured on soft substrates, extrusion of mutants is impaired on stiffer substrates. Furthermore, mutant cells at the interface of soft and stiff substrates migrate to the stiff substrate by durotaxis and evade extrusion84, suggesting that the ECM stiffness landscape may profoundly affect tumorigenesis. In another study, in the pancreatic tissue, tumorigenesis was found to depend on the tissue architecture. It was observed that in small pancreatic ducts, tumor growth was away from the duct, whereas in large ducts tumor growth was inward towards the lumen, suggesting that tension imbalance and tissue curvature may play a crucial role in epithelial tumorigenesis91 . Another study show that in stratified epithelia of skin tissue, tumor progression in the early stages is shaped by forces exerted as a result of tissue structure92. Cells with HRas mutation in mouse embryonic skin produce rigid cells with high Keratin levels which are unable to dissipate compressive forces, and hence rupture the basement membrane and invade the underlying tissue93.
To develop a framework explaining these experimental observations describing relevance of heterogeneity and stochasticity in cancer initiation, application of concepts from physics such as non-linear dynamics and critical transitions might be helpful, which will be the focus of the next section.