Prognostic and Predictive Significance of Stromal Fibroblasts and Macrophages in Colon Cancer

Abstract

Colon cancer development and malignant progression are driven by genetic and epigenetic alterations in tumor cells and by factors from the tumor microenvironment. Cancer cells become reliant on the activity of specific oncogenes and on prosurvival and proliferative signals they receive from the abnormal environment they create and reside in. Accordingly, the response to anticancer therapy is determined by genetic and epigenetic changes that are intrinsic to tumor cells and by the factors present in the tumor microenvironment. Recent advances in the understanding of the involvement of the tumor microenvironment in tumor progression and therapeutic response are optimizing the application of prognostic and predictive factors in colon cancer. Moreover, new targets in the tumor microenvironment that are amenable to therapeutic intervention have been identified. Because stromal cells are with rare exceptions genetically stable, the tumor microenvironment has emerged as a preferred target for therapeutic drugs. In this review, we discuss the role of stromal fibroblasts and macrophages in colon cancer progression and in the response of colon cancer patients to therapy.

Keywords: colon cancer; fibroblasts; macrophages; tumor microenvironment.

Figure 1

Interplay between tumor cells and stroma. Fibroblasts and macrophages secrete a variety of soluble factors that trigger oncogenic signaling in tumor cells (Wnt, STAT3, NF-κB), resulting in enhanced proliferation, migration, and resistance to therapy. Note that some factors (eg, TGFβ, IL-6) can be produced by both macrophages and fibroblasts. In turn, tumor cells can produce factors, such as TGFβ, IL-1β, and HGF (indicated by red arrows), that activate stromal cells.

Figure 2

Molecular classification of colon cancer into three main colon cancer subtypes (CCS). This approach is more accurate for guiding therapeutic decisions. For example, these classifications established that KRas mutations are not optimal criteria for the selection of patients for an anti-EGFR therapy, as the CCS3 patients fail to respond to EGFR inhibitors irrespective of the KRas status. Abbreviations: CIN, chromosomal instability; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; EMT, epithelial–mesenchymal transition.

Figure 3

Macrophages promote 5FU-induced apoptosis. (A) HCT116 and HKe-3 cells were treated with 5FU (10 μM) in the absence or the presence of THP1 macrophages (Mo) or IL-1β as indicated and the extent of apoptosis was determined after 48 hours. (B) HCT116 cells were treated with 5FU (1 μM or 10 μM) in the absence or the presence of THP1 macrophages or IL-1β as indicated for 48 hours. Cell lysates were examined for the presence of cleaved PARP, cleaved caspase-7, p53, and p21 by immunoblotting.