Inflammation and Cancer The Significance of COX-2. Dan Dixon . Dept. of Biological Sciences South Carolina Cancer Center firstname.lastname@example.org. Inflammation and Cancer. Inflammation is a critical component of tumor progression.
Dept. of Biological Sciences
South Carolina Cancer Center
Inflammation is a critical component of tumor progression
Tumors act as wounds that fail to heal
the world’s first man-made cancer on the ears of a rabbit
MonocyteSome of the Players…
Wound Healing: Normal tissues have a highly organized and segregated architecture. Epithelial cells sit atop a basement membrane separated from the vascularized stromal (dermis) compartment. Upon wounding or tissue assault, platelets are activated and form a haemostatic plug where they release vasoactive mediators that regulate vascular permeability, influx of serum fibrinogen, and formation of the fibrin clot. Chemotactic factors such as transforming growth factor- and platelet-derived growth factor, derived from activated platelets, initiate granulation tissue formation, activation of fibroblasts, and induction and activation of proteolytic enzymes necessary for remodelling of the extracellular matrix (for example, matrix metalloproteinases and urokinase-type plasminogen activator). In combination, granulocytes, monocytes and fibroblasts are recruited, the venous network restored, and re-epithelialization across the wound occurs. Epithelial and stromal cell types engage in a reciprocal signalling dialogue to facilitate healing. Once the wound is healed, the reciprocal signalling subsides.
Invasive Tumor Growth: Invasive carcinomas are less organized. Neoplasia-associated angiogenesis and lymphangiogenesis produces a chaotic vascular organization of blood vessels and lymphatics where neoplastic cells interact with other cell types (mesenchymal, haematopoietic and lymphoid) and a remodelled extracellular matrix. Although the vascular network is not disrupted in the same way during neoplastic progression as it is during wounding, many reciprocal interactions occur in parallel. Neoplastic cells produce an array of cytokines and chemokines that are mitogenic and/or chemoattractants for granulocytes, mast cells, monocytes/macrophages, fibroblasts and endothelial cells. In addition, activated fibroblasts and infiltrating inflammatory cells secrete proteolytic enzymes, cytokines and chemokines, which are mitogenic for neoplastic cells, as well as endothelial cells involved in neoangiogenesis and lymphangiogenesis. These factors potentiate tumour growth, stimulate angiogenesis, induce fibroblast migration and maturation, and enable metastatic spread via engagement with either the venous or lymphatic networks.
Ulcerative colitis (UC)
Cumulative probability (%)
Time from diagnosis (years)
Eaden JA, et al. Gut. 2001;48:526.
Insulted stromal cells recruit activated inflammatory cells
Chronic activation promotes continued inflammation, angiogenesis, and
Inflammatory cells express factors that stimulate cell growth and progression
Epoxy Acids (EETs)
Dihydroxy AcidsCyclooxygenase and Arachidonic Acid Metabolism
PGI2 INHIBITS IT
PGE2, PGF, and PGI2
PGE2 and PGI2
PGF CONTRACTS IT
PGE2 and PGI2
RENAL BLOOD FLOW
PGE2 and PGI2
PGE2 and PGF
PGI2 RELAXES ITProstaglandin Regulate Physiological Functions
Prostaglandins are biologically active phospholipid molecules that regulate many physiological functions
Proper balance of prostaglandins are critical for normal homeostasis
Prostaglandins control cellular function through G-coupled membrane receptors and nuclear receptors
COX-1: Constitutively present
COX-2: Inducible isoform
“COX-3”: Splice variant of COX-1
Protein Size 72 kDa 72/74 kDa
Gene Size 22 kb 8.3 kb
mRNA size 2.7 kb 4.5 kb; contains multiple AU-rich elements in 3’UTR
Localization ER, nuclear envelope ER, nuclear envelope
Cell & Tissue Expression Platelets, stomach, kidney, Expressed in most cells or tissues after stimulation with
colon, most tissues cytokines, growth factors, or tumor promoters
Gene Regulation Constitutive low-level expressionImmediate-early response gene, rapidly transcribed,
mRNA is rapidly degraded, translation is controlled
w Decreased risk of CRC-associated deaths in aspirin users.
w The NSAID sulindac decreases the size and number of polyps (FAP).
w Prostaglandin levels are increased in CR tumors.
w Overexpression of COX-2 detected in adenomas and adenocarcinomas.
wMin mice and AOM-treated rats have elevated COX-2 levels.
w Sulindac and other NSAIDs attenuate intestinal tumor and xenografted cancer cell growth in mice.
w Overexpression of COX-2 in epithelial cells results in:
Angiogenesis (increased VEFG, FGF, PDGF… expression)
Metastatic potential (increased adhesion and MMP expression)
w Mice defective in COX-2 have a dramatic reduction (86%) in colorectal polyp formation.
COX-2 protein staining in colon tumor
Normal colon epithelium
COX-2-derived PGs promote cell growth, proliferation, and angiogenic gene expression in cells composing a tumor
Total Polyp Number/Mouse
GenotypeGenetic “Removal” of COX-2 Suppresses Tumorigenesis
Early AdenomaInvolvement of COX-2 in the Progression of Colon Cancer
Loss of COX-2 gene regulation
Increased PG levels
Suh 1993, men
Suh 1993, women
Muscat 1994, men
Muscat 1994, women
Relative Risk of Colorectal CancerLong-Term Aspirin and NSAID Use Reduces The Risk of Developing Colorectal Cancer
adapted from Thun et al, JNCI, 2002
Made by several companies
Motrin®, Advil®, Motrin IB®
Purpose-designed selective inhibitors of COX-2: the COXIBs.
Although rofecoxib (Vioxx) has been withdrawn, celecoxib (Celebrex) and valdecoxib (Bextra) remain on the US market.
Lumiracoxib and etoricoxib remain under consideration by the FDA.
Schematic depiction of the structural differences between the substrate-binding channels of COX-1 and COX-2 that allowed the design of selective inhibitors
Grosser, T. et al. J. Clin. Invest. 2006;116:4-15
Vioxx associated w/higher risk of CV events
No difference in CV events
Colon Cancer Studies
2-fold increase risk of CV-events.
Vioxx removed from market.
2.5-fold increase risk of CV-events.
FDA recommends limited use of Celebrex and Bextra.
No difference in CV eventsCOXIBs are not without their problems…
Summary of relevant trials examining CV events associated with extended COXIB use
After 18 months increases CV events were detected and led to removal of Vioxx from the market.
Confirmed Cardiovascular Events with Extended Vioxx Use
The APPROVe study compared Vioxx vs. placebo in the prevention of colon cancer