Multifocal epithelial tumors and field cancerization: stroma as a primary determinant

Abstract

It is increasingly evident that cancer results from altered organ homeostasis rather than from deregulated control of single cells or groups of cells. This applies especially to epithelial cancer, the most common form of human solid tumors and a major cause of cancer lethality. In the vast majority of cases, in situ epithelial cancer lesions do not progress into malignancy, even if they harbor many of the genetic changes found in invasive and metastatic tumors. While changes in tumor stroma are frequently viewed as secondary to changes in the epithelium, recent evidence indicates that they can play a primary role in both cancer progression and initiation. These processes may explain the phenomenon of field cancerization, i.e., the occurrence of multifocal and recurrent epithelial tumors that are preceded by and associated with widespread changes of surrounding tissue or organ "fields."

Figure 1. Potential determinants of multifocal and recurrent epithelial cancer and field cancerization.

Aging and environmental insults, such as UV irradiation or smoke, can target both epithelial and stromal compartments of organs, leading to stable genetic and epigenetic changes. Cross-talk between these two compartments can induce further pro-oncogenic alterations, such as secretion of growth factors and proteases, alterations in the extracellular matrix, and recruitment of inflammatory cells. These spreading alterations in both the epithelium and stroma are a phenomenon known as field cancerization.

Figure 2. Converging control of CAF activation by multiple signaling pathways.

Activation of a CAF phenotype results in the increased stromal expression of a battery of molecules (representative ones are indicated in the center circle) that enhance epithelial cancer development and progression. These changes can be the combined result of several extracellular signals triggered by direct exogenous insults (smoke products, UV) or indirectly by a battery of growth factors and cytokines produced by neighboring cells (incipient epithelial cancer cells, immune/inflammatory cells). Signal amplification can then take place through a number of intermediate cytoplasmic events, like activation of kinase cascade pathways and production of ROS. Finally, establishment of a CAF phenotype is critically dependent on control of gene expression through a battery of transcription factors and epigenetic changes functioning in either a positive or negative manner. As discussed in the text, two of these pathways, linking extracellular signals to control of gene transcription, have been implicated so far in primary stromal alterations leading to epithelial cancer development. Mesenchymal loss or alterations of TGF-β/Smad signaling lead to gastric and prostate cancerous lesions (137), while compromised Notch/CSL signaling results in multiple keratinocyte tumors and skin field cancerization (94). The surprising organ-selective effects remain to be understood but could be due to heterogeneity of CAF cells of origin.

Figure 3. The seed and soil hypothesis in multifocal and recurrent epithelial cancer.

Multifocal and recurrent epithelial cancer may be analogous to a difficult to eradicate weed. (A) The theory of seed implantation suggests that multifocal recurrent tumors may be due to the ability of monoclonal cancer cells (seeds) to root deeply into the terrain and spread locally as well as disseminate to distant sites. Much like weeds, these tumor cells can grow under many conditions. (B) In contrast, the bad soil hypothesis suggests that insults and alterations in the stroma generate highly permissible soil that allows for the growth of multiple tumors of monoclonal or polyclonal origin (field cancerization). According to this latter view, unless the soil is corrected, various forms of prevention or intervention would be of little use in treating such cancers.