Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis.

In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/ß-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.

Mesenchymal Cells in Colon Cancer.

Mesenchymal cells in the intestine comprise a variety of cell types of diverse origins, functions, and molecular markers. They provide mechanical and structural support and have important functions during intestinal organogenesis, morphogenesis, and homeostasis. Recent studies of the human transcriptome have revealed their importance in the development of colorectal cancer, and studies from animal models have provided evidence for their roles in the pathogenesis of colitis-associated cancer and sporadic colorectal cancer. Mesenchymal cells in tumors, called cancer-associated fibroblasts, arise via activation of resident mesenchymal cell populations and the recruitment of bone marrow-derived mesenchymal stem cells and fibrocytes. Cancer-associated fibroblasts have a variety of activities that promote colon tumor development and progression; these include regulation of intestinal inflammation, epithelial proliferation, stem cell maintenance, angiogenesis, extracellular matrix remodeling, and metastasis. We review the intestinal mesenchymal cell-specific pathways that regulate these processes, with a focus on their roles in mediating interactions between inflammation and carcinogenesis. We also discuss how increasing our understanding of intestinal mesenchymal cell biology and function could lead to new strategies to identify and treat colitis-associated cancers.

IKKß acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis.

Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-κB gene signature in CAFs has been suggested to promote tumorigenesis in models of pancreatic and mammary skin cancer. Using an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we now provide evidence for a tumor-suppressive function of IKKß/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkß stimulates intestinal epithelial cell proliferation, suppresses tumor cell death, enhances accumulation of CD4(+)Foxp3(+) regulatory T cells, and induces angiogenesis, ultimately promoting colonic tumor growth. In Ikkß-deficient fibroblasts, transcription of negative regulators of TGFß signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFß gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkß-deficient fibroblasts prevents HGF secretion, and pharmacological inhibition of Met during the CAC model confirms that enhanced tumor promotion is dependent on HGF-Met signaling in mucosa of Ikkß-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKß/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients.