Field Carcinogenesis in Cancer Evolution: What the Cell Is Going On?

Abstract

Field carcinogenesis describes the prevalence of tumor-related alterations in normal appearing tissues. Here, we summarize recent efforts in profiling molecular field dynamics for resolving early events in cancer evolution. We also highlight gaps in our knowledge of the molecular and cellular heterogeneity of field carcinogenesis and propose directions to tackle these voids using single-cell-based approaches and unique tissue sampling models. By interrogating both the mutagenized epithelium and its microenvironment, we surmise that single-cell-guided studies will help chart the spatiotemporal molecular and cellular "atlas" of field carcinogenesis, will further delineate preneoplastic initiation and progression, and will help identify cancer prevention and early intervention targets.

Figure 1.

A panoramic model of field carcinogenesis at single-cell resolution. This model shows the inception of field carcinogenesis in normal-appearing epithelium and how this phenomenon may be influenced by or modulate the surrounding microenvironment. These field effects may be markers for the progression of normal-appearing mutagenized cells in the field into histologically-distinguishable premalignant states, and later, malignant stages. Epithelial cancerization fields may comprise different subtypes of normal epithelial cells (left) resulting in clones of mutagenized cells that carry diverse genomic alterations (rough-appearing cells with dotted nuclei). Fit mutagenized clones overcome selective pressure leading to clonal expansion and progression of the normal or premalignant field into premalignant lesions and later, malignant tumors. The model also depicts diverse cell types, populations, and components of the immune and stromal microenvironments whose dynamic interplay with field carcinogenesis in the epithelium can be best illustrated at the single-cell level. Changes in stromal compartments such as fibroblasts (e.g. increased cancer-associated fibroblasts), extracellular matrix components, as well as vasculature may be further “fuel” for field carcinogenesis or be impacted by mutagenized field epithelia. Additionally, it is speculated that co-evolution of the immune microenvironment may play important roles in field cancerization and progression. Possible early immune-response dynamics may include gradual changes to immune cell abundance and/or epithelial infiltration, which could be decreased (e.g. for natural killer, dendritic, and T cells), or potentially increased (e.g. for tumor-associated macrophages, and regulatory and exhausted T lymphocytes-such as through the increased expression of inhibitory checkpoints). This can be also accompanied by an increased expression of inhibitory immune checkpoints, or production of pro-tumor immunomodulatory molecules such as cytokines and antibodies. UV: ultraviolet; DC: dendritic cell; NK: natural killer cell; TAM: tumor-associated macrophage; T_RM: tissue-resident memory T cell; T-reg: regulatory T cell; CAF: cancer-associated fibroblast; ECM: extracellular matrix. Created with BioRender.com.