Tumor development involves a complex interplay between cancer cells and the surrounding microenvironment, including cancer-associated fibroblasts (CAFs). Whether such CAFs are tumor suppressive or tumor promoting remains a contentious issue, with obvious therapeutic implications regarding targeting of stromal cell populations in vivo.
In colorectal cancer, inflammation is strongly implicated in tumorigenesis. The NF-κB signaling pathway is of particular interest, as a key regulator of both inflammation and cancer. Previous studies from the group of Florian Greten and others have assessed the function of NF-κB signaling in intestinal epithelial cells at different stages during tumor growth. Two new studies, in this issue, have now investigated the stromal contribution of NF-κB signaling to colorectal tumorigenesis through deletion of the same gene in mesenchymal cells—with diametrically opposite results. Both groups took a broadly similar approach by deleting IKKβ (a mediator of NF-κB) in intestinal fibroblasts/CAFs, alongside chemical carcinogenesis (AOM/DSS). Using a ColVICre driver, Koliaraki et al. report that deletion of IKKβ in intestinal mesenchymal cells leads to decreased tumor incidence. Conversely, Pallangyo et al. report that deletion of IKKβ using a Col1a2Cre-ER driver stimulates intestinal epithelial cell proliferation and increased tumor size, suggesting an unexpected tumor-suppressive function for NF-κB signaling in CAFs. Interestingly, in the absence of inflammation, both models show no overt phenotype at homeostasis, suggesting that tissue damage is required.
This work can be put in the context of growing literature where the inhibition of stromal elements is hard to predict. For example, in pancreatic ductal adenocarcinoma (PDAC), activated stellate cells alter the tumor microenvironment, making the tumor refractory to drug treatment. It follows that depletion of the stroma should lead to therapeutic improvement. However, through targeted functional ablation of myofibroblasts, Raghu Kalluri and colleagues have revealed a tumor-suppressive role for the stroma in PDAC. In the mammary gland, Gustavo Leone’s group has shown that genetic inactivation of Pten in stromal fibroblasts accelerates the progression of mammary epithelial tumors. In the intestine, Tomi Mäkelä and colleagues have shown that LKB1 signaling in mesenchymal cells is required for suppression of gastrointestinal polyposis, whereas Gijs van den Brink’s group showed that Indian Hedgehog signaling from the stroma is required for adenoma formation. Therefore, a much more detailed study of the tumor-suppressive and tumor-promoting aspects of the tumor stroma is required, and this is likely to be tissue-tumor specific. Care should be taken in overinterpreting depletion studies, which may have dramatic effects on homeostasis.
Clearly work remains to reconcile these two new studies, specifically to determine if IKKβ is being deleted in distinct fibroblast populations through the use of different Cre drivers. Furthermore, it is possible that constitutive (ColVICre) versus inducible (Col1a2Cre-ER) deletion of IKKβ could have biological implications, particularly regarding genetic compensation mechanisms through development. Uniform analysis using the same conditionally inducible Cre driver, sampled at the same time point, will be essential here. Most importantly though, these results suggest there is heterogeneity in intestinal fibroblasts and that targeting pathways may have distinct outcomes in different fibroblast populations.
Together, these two studies offer very exciting new insights into NF-κB signaling in stromal fibroblasts in colitis-associated cancer and show that we are only just beginning to understand the complexity of the tumor microenvironment. Understanding the differences between these studies could offer profound new insights into fibroblast heterogeneity in the intestinal epithelium.
