Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Abstract

Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

Fig. 1

Multistage tumorigenesis. In normal tissue, somatic mutations sporadically arise and either are eliminated by tumor-suppressive mechanisms or gain proliferative advantages to form clones. The mutant clones can still maintain homeostasis until they are exposed to additional stimulus. Their proliferation becomes uncontrolled, and malignant transformation initiates, progressing from premalignant lesions to advanced tumors. During this process, the transformed cells gradually accumulate additional genetic mutations and epigenetic alterations, exhibiting increasingly malignant traits such as immune evasion, structural disruption, and invasion. Simultaneously, the microenvironment of these cells evolves from being tumor-suppressive to supportive of malignancy. This includes dysfunctional immunosurveillance, the emergence of tumor-promotive inflammation, gradual transformation of fibroblasts to CAFs, as well as stiffening of the ECM. CAF cancer associated fibroblast, TAM tumor associated macrophages, MDSC myeloid-derived suppressor cell, ECM extracellular matrix. Created with BioRender.com

Fig. 2

Research history of tumor initiation and early tumorigenesis. The upper section emphasizes the role of somatic mutations in tumorigenesis, while the lower section demonstrates the evidence of the driver events beyond genetic events. ICGC the International Cancer Genome Consortium, TCGA the Cancer Genome Atlas, PCAWG the Pan-Cancer Analysis of Whole Genomes, HTAN the Human Tumor Atlas Network

Fig. 3

Interactions between oncogenic driver events. a In addition to genotoxicity, chemical and radical insults can induce cell injury, differentiation, and apoptosis. Oncogenic mutations that can confer resistance to such injuries provide proliferative advantages. On the other hand, the insults stimulate proliferative and self-renewal pathways by transcriptional and epigenetic regulation. Immune cells can also be activated to regulate transformed cell fate and promote tumorigenesis. b Unhealthy diet patterns induce hyperglycemia and hyperinsulinemia, and further cause differential response to insulin signals, which can facilitate cells harboring Src or Ras mutation in gaining competitive advantages and promote tumorigenesis. High levels of fatty acids also promote retention of Ras-mutant cells in cell competition by metabolism remodeling and mitochondrial membrane potential restoration. In addition, fatty acid and glucose participate in tumorigenesis as signaling molecules by modulating immune response and inflammation. c Microbiota interacts with transformed cells to affect host DNA methylation, transcription, metabolism and immune microenvironment to have an influence on malignant transformation. d Aging induces senescent stromal cells to secrete SASPs, which can reverse the outcome of cell competition and promote EMT of the mutant cell. Aging also cause spontaneous methylation, further promoting mutation-driven tumorigenesis. e The pathological processes mentioned above can converge at inflammation, which releases tumorigenic potential of expansive clones by activating oncogenic pathways and increases epigenetic plasticity. For instance, in pancreatic inflammation induced plastic state, ADM, Kras-mutant cells are more likely to transform to malignant status, while in the absence of inflammation, Kras can only induce PanIN without progression to PDAC. EMT epithelial-to-mesenchyma transition, ROS reactive oxygen species, nAChR nicotinic acetylcholine receptor, MDSC myeloid-derived suppressor cell, PDK pyruvate dehydrogenase kinase, TCF4 T cell factor 4, HGF hepatocyte growth factor, TET2 tet methylcytosine dioxygenase 2, EGFR Epidermal growth factor receptor, UV ultraviolet, Gata6 GATA Binding Protein 6, EZH2 enhancer of zeste homolog 2, PPAR-δ peroxisome proliferator-activated receptor-delta, FGF21 fibroblast growth factor 21, CCL2 PDK4, pyruvate dehydrogenase kinase 4, ADM acinar-to-ductal metaplasia, PanIN pancreatic intraepithelial neoplasms, PDAC pancreatic ductal adenocarcinoma, ETBF enterotoxigenic Bacteroides fragilis, Created with BioRender.com

Fig. 4

Cell-autonomous processes in tumorigenesis. After acquiring genetic and epigenetic mutations, transformed cells enter a malignant continuum where they reprogram their developmental pathways, allowing gradually gains of uncontrollable self-renewal capabilities and aberrant differentiation potential, primarily through three mechanisms: originating from stem cells, dedifferentiating from lineage-committed cells, and hijacking intermediate states during trans-differentiation. Created with BioRender.com

Fig. 5

Cell competition across tissues. a Live cells can be extruded from simple intestinal epithelium by intercellular communications and cytoskeleton rearrangement. b Intestinal stem cells compete for dominance within the stem cell niche located at the bottom of the intestinal crypt. Mutant supercompetitors are more likely to maintain stemness, replace wild-type counterparts, occupy the ISC niche, and subsequently take over the entire crypt. The displaced wild-type cells, referred to as “losers,” differentiate, migrate upward along the crypt, and are ultimately shed at the top. The fate of stem cells can be regulated by secretory signals that come directly from supercompetitors and indirectly from stromal cells surrounding the crypts, stimulated by the supercompetitors. Stemness inhibitory signals, including BMP activators and NOTUM, differentially affect wide-type cells and supercompetitors by preventing wild-type cells from maintaining stemness, while having less effects on supercompetitors. c In stratified epithelium, the outcome of stem cell competition is also regulated by cell fate decisions. However, it is not limited to specific microstructure as the crypt, the winner clone has the potential to expanding to a large area. WT wild-type cells, BMP bone morphogenic protein, ISCs intestinal stem cells. Created with BioRender.com

Fig. 6

Interactions of transformed cell and microenvironmental components. a Abnormal genetic, epigenetic and transcriptional signals in transformed cells can paradoxically induce immune activation, while simultaneously developing strategies to achieve immune evasion. Their crosstalk is primarily mediated by direct cell-cell interaction signals and paracrine signals, such as chemokines, cytokines and growth factors and direct cell-cell interaction signals. As a positive feedback, tumor supportive immune cells, such as TAMs, which can produce IL-1β signals to further promote malignant evolution. b Transformed cells, along with environmental stress and genetic alterations, can activate fibroblasts through both secretory and contact signals, transforming them into CAFs with diverse tumor-promoting properties. In turn, fibroblasts secrete stemness signals to differentially regulate mutant and wild-type cells during cell competition. c Environmental signals can induce ECM remodeling, and a single transformed cell with ECM adhesion loss can also produce ECM to support its survival. In turn, abnormal mechanical signals in the ECM, including stiffness and viscoelasticity, under pathological conditions such as inflammation, aging, wound repair, and T2DM, predispose mutant cells to malignant progression through the activation of the YAP/TAZ pathway. The pro-tumorigenic effects can be aggravated by mutations in the RTK-Ras pathway. Additionally, a stiff ECM inhibits filamin from translocating from perinuclear areas to the interface of wild-type and mutant cells, further inhibiting the extrusion of mutant cells. TAMs tumor associated macrophages, MDSC myeloid-derived suppressor cell, cGAS cyclic GMP-AMP synthase, STING stimulator of interferon genes, IRF3 IFN regulatory factor 3, T2DM type 2 diabetes mellitus, Yap yes-associated protein, TAZ transcriptional co-activator with PDZ-binding motif, LPAR4 lysophosphatidic Acid Receptor 4. Created with BioRender.com

Fig. 7

Tissue architecture restraint for clone expansion and alterations in tumorigenesis. a Cell density sensing mechanisms trigger apoptosis in cells sensitive to compaction, whether mutant or wild-type. b Mutations that disrupt the ECM and enable anchorage-independent survival allow cells to move to the lumen and expand. Additionally, the loss of cell-cell junctions can unleash the proliferative potential of mutations in situ instead of through translocation. c Mutant intestinal crypts are more likely to split rather than merge, increasing their number but still keeping overall balance through spreading and decreasing local crypt density. The Kras mutation speeds up this splitting, to a degree that cannot be counteracted by dispersal, leading to tumorigenesis. d When the homeostatic tissue architecture is disrupted, the mutant cells mediate a dysregulated tumor structure. This manifests as alterations in cell-cell junctions, cell-ECM adhesions and cytoskeleton rearrangement. The initial tissue curvature, as well as the stiffness of the basal membrane and suprabasal cells, all affect the nascent tumor morphogenesis. In addition, the EMT mediated by EFNB1-EPHB4 interactions in epithelial cells harboring TP53 mutations occurs alongside early malignant morphogenesis. MMP metalloprotease, EMT epithelial-to-mesenchymal transition. Created with BioRender.com