SyndromesinvolvingdefectsinthehomologousrecombinationDNArepairsystemconstituteagroupofdisorders—Bloomsyndrome,ataxia-telangiectasia,andFanconianemia—thatarecharacterizedbyhypersensitivitytoDNA-damagingagents,suchasionizingradiation.BRCA1 andBRCA2, whicharemutatedinfamilialbreastcancers,alsoareinvolvedinhomologousDNArepair.
Mutationsincurredinlymphocytesexpressinggeneproductsthatinducegenomicinstability(RAG1,RAG2,AID)areimportantinthepathogenesisoflymphoidneoplasms.
Infiltrating cancers provoke a chronic inflammatory reaction. In patients with advanced cancers, this inflammatory reaction can be so extensive as to cause systemic signs and symptoms, such as anemia (the so-called “anemia of chronic disease”), fatigue, and cachexia. However, studies carried out on cancers in animal models suggest that inflammatory cells also modify the tumor microenvironment to enable many of the hallmarks of cancer. These effects may stem from direct interactions between inflammatory cells and tumor cells, or through indirect effects of inflammatory cells on other resident stromal cells, particularly cancer-associated fibroblasts and endothelial cells. Proposed cancer-enabling effects of inflammatory cells and resident stromal cells include the following:
Release of factors that promote proliferation. Infiltrating leukocytes and activated stromal cells have been shown to secrete a wide variety of growth factors, such as EGF, and proteases that can liberate growth factors from the extracellular matrix (ECM).
Removal of growth suppressors. As mentioned earlier, the growth of epithelial cells is suppressed by cell–cell and cell–ECM interactions. Proteases released by inflammatory cells can degrade the adhesion molecules that mediate these interactions, removing a barrier to growth.
Enhanced resistance to cell death. Detachment of epithelial cells from basement membranes and from cell–cell interactions can lead to a particular form of programmed cell death called anoikis. It is suspected that tumor-associated macrophages may prevent anoikis by expressing adhesion molecules such as integrins that promote direct physical interactions with tumor cells.
Angiogenesis. Inflammatory cells release numerous factors, including VEGF, that stimulate angiogenesis.
Invasion and metastasis. Proteases released from macrophages foster tissue invasion by remodeling the ECM, while factors such as TNF and EGF may directly stimulate tumor cell motility. As mentioned earlier, other factors released from stromal cells such as TGF-β may promote epithelial-mesenchymal transition (EMT), which may be a key event in the process of invasion and metastasis.
Evasion of immune destruction. A variety of soluble factors released by macrophages and other stromal cells are believed to contribute to an immunosuppressive tumor microenvironment. The leading suspects include TGF-β and other factors that either favor the recruitment of immunosuppressive T regulatory cells or suppress the function of CD8+ cytotoxic T cells. Furthermore, there is abundant evidence in cancer models and emerging evidence in human disease that advanced cancers contain mainly alternatively activated (M2) macrophages (Chapter 3). M2 macrophages produce cytokines that promote angiogenesis, fibroblast proliferation, and collagen deposition, all of which are commonly observed in invasive cancers and in healing wounds, giving rise to the notion that cancers are like “wounds that do not heal.”
A thorough understanding of how cancers “manipulate” inflammatory cells to support their growth and survival remains elusive. However, the results from animal studies are intriguing and raise the possibility of therapies directed at tumor-induced inflammation and its downstream consequences. An example of one such intervention involves aspirin and other COX-2 inhibitors, use of which is associated with a decreased risk of colorectal cancer in several epidemiological studies.