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Download Tumor Angiogenesis in Colorectal Cancer
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Tumor Angiogenesis in Colorectal Cancer Metastatic colorectal cancer (mCRC) is the third leading cause of cancer-related deaths in the United States. Treatment algorithms must be updated to accommodate all targeted and antiangiogenic agents as potential therapy for patients with mCRC. 1. Cancer cells release growth factors that activate endothelial cells during the switch to the angiogenic phenotype. This occurs in response to acquired gene mutations and hypoxia. 2. Growth factors bind to endothelial cell receptors, activating signal transduction pathways and causing cell proliferation. 3. Tumor blood vessels are characteristically tortuous, saccular, and leaky; blood flow is uneven and chaotic, with areas of tumor necrosis, hypoxia, and acidosis. www.scienceofcrc.org Common Sites of Spread Liver Vascularized Tumor Blood vessels feed tumor growth Blood vessels sprouting Angiogenesis in CRC liver metastases is initiated when a tumor co-opts sinusoidal endothelial cells lining the periphery of the lesion. The liver contributes abundant proangiogenic factors to the metastatic lesion. Metastases Lungs Early cancer Colon 3 1 Release of growth factors Liver Polyps 2 Colon Tumor Rectum spread (metastasis) A tumor in its early stages of development cannot grow past a few millimeters in diameter unless it is fed by blood vessels. Bone Lymph Nodes Treatments for Metastatic Colorectal Cancer Targeted Therapies Targeted cancer therapies halt the growth and spread of cancer by “targeting,” or interfering, with specific molecules that play a role in tumor progression and growth. In addition to the targeted treatments that have already gained FDA approval, numerous other agents such as monoclonal antibodies, engineered proteins, tyrosine kinase inhibitors (TKIs) and other small molecule agents with varying mechanisms of action are currently under investigation as potential therapy for patients with mCRC. Biopsy/Genetic Test Chemotherapy Available EGFR inhibitors are ineffective in tumors that carry mutations of the KRAS gene. Roughly 40% of colorectal cancers have KRAS mutations. Anti-EGFR Fusion Protein Antibody EGF FGF FGFR PDGF PDGFR-β Antibody ANG-2 VEGF B PlGF TIE-2 VEGFR1 EGFR VEGF A VEGF C VEGFR2 VEGF D VEGFR3 Tyrosine Kinase Inibitor Ras Raf Braf* Akt mTOR Vessel Regression ERK Anti-EGFR therapy attacks the growth signals that encourage proliferation of cancer cells. ANGIOGENESIS TUMOR MICROENVIRONMENT ENDOTHELIAL CELL: The VEGF family (A-D) binds to receptors VEGFR-1, VEGFR-2, VEGFR-3, activating signal transduction to promote angiogenesis, vasculogenesis, and lymphangiogenesis. Fusion Protein Radiation Antiangiogenic Therapy 1. Tumor Shrinkage Metastatic tumors often shrink significantly with targeted treatments. Without a blood supply, the tumors cannot sustain themselves. PI3K MEK Chemotherapy attacks the cancer cells directly, causing them to die off. Potential Outcomes of Targeted Therapies Antibody VEGF B FGF PlGF EGF VEGF A RET VEGFR EGFR Antibody 2. Stop Tumor Growth Primary tumors are also affected by targeted treatments. As the vessels feeding the tumor shrink back, cells in the tumor mass are starved for oxygen and nutrients. Tumor growth is stopped and the surrounding environment becomes more stable. KIT FGFR Dying Cells Tyrosine Kinase Inibitor Ras Raf MEK Braf* PI3K Src Akt Rac1 mTOR Stabilized cell environment JNK ERK ONCOGENESIS ANGIOGENESS TUMOR MICROENVIRONMENT Radiation therapy kills cancer cells with high-energy rays. This resource was independently developed with grants from Bayer Pharma AG, Genentech, and Regeneron. © 2013 by The Angiogenesis Foundation. All Rights Reserved. TUMOR CELL: Multiple growth factors and receptors activate signal transduction and cell cycle pathways that stimulate tumor cell growth. Antiangiogenic therapies attack the blood vessels that feed the tumor. ANG = Angiogenin; EGF = Epidermal Growth Factor; FGF = Fibroblast Growth Factor; PDGF = Platelet-Derived Growth Factor; PlGF = Placental Growth Factor; VEGF = Vascular Endothelial Growth Factor 3. Disease Progression Tumors may continue to grow despite treatment. This is called “non-response” to treatment.
