Contributed by Katherine Sippel, Ph.D.
Historically, the mechanism for tumorigenesis is attributed to DNA damage resulting in misregulation and over-proliferation of certain cell types. Mutagenic chemicals or UV radiation are traditionally considered to be the agents that cause cancer; however the list of carcinogens has developed rapidly to include immune stressors and infections like human papillomavirus or Helicobacter pylori. The recent inclusion of these factors indicates that there are deeper underlying mechanisms that can contribute to cancer development. In light of this, a growing number of studies have sought out a more unified oncogenic mechanism, and the culprit that is emerging is chronic inflammation.
The immune system is a complex and uniquely evolved system that exists to identify infection and remove it quickly. One part of that process is the secretion of cytokines that recruit immune cells and trigger defensive signaling pathways in proximal cells. However, defensive signaling and prolonged exposure to cytokines caused by stress, chemicals, and even non-symptomatic infections can protract the body's response causing ill and far-reaching effects. For instance, cytokines including TNF-α and Interleukins (ILs) mediate their signals through chemokine receptors to activate NF-kappaB leading to the upregulation of factors such as cyclooxygenase (COX)-2, 5-lipoxygenase (LOX), and matrix metalloproteinases (MMPs). Increased expression of these factors has been shown to transform cells oncogenically, confer chemoresistance, maintain proliferation, enhance angiogenesis, and promote metastasis in tumor cells.
Additionally, the increased production of chemokines (CCLs and CXCLs) recruits a number of immune cells including circulating monocyte-derived macrophages, myeloid-derived suppressor cells and regulatory T-cells. The presence of these cells can promote extravasation, act as an immunosuppressant, promote neovascularization, and enhance migratory activity resulting in metastasis.
As more cancer sources are discovered, particularly those associated with asymptomatic and therefore undiagnosed infections, it becomes apparent that we need to make continued efforts to understanding the role of inflammation in tumorigenesis and cancer progression. This work could pave the way to developing better chemotherapeutics and even cancer prevention.
Selected Reviews:Bharat B. Aggarwal, Shishir Shishodia, Santosh K. Sandur, Manoj K. Pandey, Gautam Sethi. Inflammation and cancer: How hot is the link? Biochemical Pharmacology 72 (2006) 1605–1621.
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