Inducing Angiogenesis Presentation.pptx cancer management

Inducing Angiogenesis Presentation.pptx

1. Inducing Angiogenesis Presented By RICHARD KIBE and KINARA TIM September 26 th , 2024

2. Introduction Angiogenesis is the physiological process by which new blood vessels are formed from pre-existing blood vessels . Neo-angiogenesis , specifically in the context of cancer, describes the abnormal formation of new blood vessels that supply nutrients and oxygen to tumors. This process is often stimulated by the hypoxic conditions within the tumor microenvironment and is critical for tumor growth and metastasis .

3. Introduction cont’ Angiogenesis plays a crucial role in the process of tumor genesis, because solid tumor need a blood supply if they are to grow in size. A mix of pro-angiogenic and anti-angiogenic factors controls how things work . Key factors include growth factors like VEGF [A,B,C &D]that stimulate neo-angiogenesis. The physiological role is crucial for normal bodily functions like wound healing, pregnancy and tissue regeneration . Pathological role plays a significant part in diseases, notably cancer, rheumatoid arthritis and diabetic retinopathy .

4. The progression of the canceration through angiogenesis. Rapid tumor growth reduces oxygen supply, creating a hypoxic microenvironment that triggers excessive angiogenesis by increasing pro-factors like VEGF, PDGF, FGF, and angiopoietin. New blood vessels then deliver oxygen and nutrients, supporting tumor survival and growth. As the tumor becomes more aggressive, it continues to proliferate, spread, and induce further angiogenesis, leading to invasion and metastasis via blood circulation.

5. Process of Angiogenesis Phases of angiogenesis begin with endothelial cell activation, where cells differentiate from angioblasts . Endothelial cells migrate and increase during the sprouting and branching phase . Signaling molecules guide the formation of new vessel structures. Tumor Dependence: Tumor growth, invasion, and metastasis depend heavily on angiogenesis. Tumors trigger new blood vessel formation to receive necessary oxygen and nutrients, especially once they exceed 1-2 mm³ in size ​. Vascular remodeling involves the stabilization and maturation of newly formed blood vessels . Key players include endothelial cells , which line the blood vessels. Pericytes and mural cells provide structural support and regulation to the developing vessels.

6. Quiescent state in Angiogenesis In the quiescent state , endothelial cells of blood vessels are dormant, and angiogenesis is repressed . Characteristics : This state is maintained by a balance between angiogenic inhibitors (like thrombospondins) and low levels of growth factors. It represents a non-angiogenic phase of tumor development . Tumor Microenvironment: Tumors in this state are not aggressive because they rely on oxygen and nutrients diffused from nearby tissues. Hypoxia eventually triggers the angiogenic switch to promote vascular growth.

7. Angiogenic Switch Angiogenic Switch : The angiogenic switch refers to the transition of a tumor from a quiescent state (non-angiogenic) to an angiogenic state, characterized by the rapid formation of blood vessels . Mechanism : This is initiated by the imbalance between pro-angiogenic factors (like VEGF) and anti-angiogenic factors, tipping towards pro-angiogenesis to support tumor growth . Clinical Significance: The angiogenic switch is critical in tumor progression as it allows tumors to grow beyond a few millimeters by acquiring a blood supply. This switch is regulated by genetic and micro-environmental changes.

8. Role of P53 in Angiogenesis Tumor Suppressor p53 plays a dual role in inhibiting angiogenesis : Induction of Anti-Angiogenic Factors : P53 upregulates anti-angiogenic molecules such as thrombospondin-1 (TSP-1), which suppresses blood vessel formation . VEGF Suppression : It downregulates VEGF, reducing the tumour's ability to stimulate new vessel growth . Mutation Impact: When P53 is mutated, its anti-angiogenic effects are lost, leading to enhanced angiogenesis and tumour growth.

9. HIF-1 (Hypoxia-Inducible Factor-1) in Angiogenesis HIF-1 is a transcription factor activated under hypoxic conditions, common in rapidly growing tumors . Mechanism : Under low oxygen, HIF-1α stabilizes and dimerizes with HIF-1β. This complex binds to hypoxia-response elements (HREs) in target genes, including those for VEGF, stimulating angiogenesis . HIF-1 also promotes the expression of other pro-angiogenic factors like PDGF, aiding the creation of new blood vessels . Clinical Significance : Overexpression of HIF-1α is correlated with tumor progression, poor prognosis, and resistance to therapy. Targeting HIF-1 is an emerging therapeutic strategy in cancer ​.

10. Process of Angiogenesis Illustration

11. Mechanisms of Angiogenesis Tumour Microenvironment : Hypoxia, ischemia, and metabolic stress stimulate angiogenesis . Tumour Vascularization : When a tumour reaches 1-2 mm³, it requires angiogenesis for further growth . Impact on Tumour Progression : New blood vessels supply oxygen and nutrients, enabling rapid tumour growth Pro-angiogenic Factors : VEGF, PDGF, IGF, FGF , and angiopoietins . Process: Basement membrane degradation . Endothelial cell activation, proliferation, and migration . Formation of new vascular networks.

12. Modes of Tumor Angiogenesis Sprouting angiogenesis: Formation of new branches from existing vessels (most common ). Intussusceptive angiogenesis: Splitting of an existing vessel . Vessel co-option: Tumors use existing vessels without forming new ones . Vasculogenic mimicry : Tumor cells form vessel-like structures . Lymphangiogenesis : Formation of new lymphatic vessels . Trans-differentiation : Cancer cells transform into endothelial-like cells

13. Angiogenic signaling pathway: VEGF/VEGFR Pathway VEGF/VEGFR Pathway : Vascular Endothelial Growth Factor (VEGF) is the central regulator of angiogenesis . VEGF family includes VEGF-A (most important in tumors), VEGF-B, VEGF-C, and VEGF-D . VEGFRs (VEGFR-1, VEGFR-2, VEGFR-3) are tyrosine kinase receptors that mediate angiogenesis. VEGFR-2 : Primary driver of endothelial cell proliferation, migration, and survival . VEGFR-3 : Key regulator of lymphangiogenesis. Therapeutic Target : VEGF inhibitors (e.g., Bevacizumab) are used to block tumour blood vessel formation

14. PDGF/PDGFR Pathway and FGF/FGFR Pathway PDGF/PDGFR Pathway: Platelet-Derived Growth Factor (PDGF) promotes recruitment of pericytes and smooth muscle cells to stabilize new blood vessels . PDGFRs : critical for vascular maturation. Significance in Therapy : PDGF inhibitors help prevent blood vessel maturation, complementing VEGF inhibition. FGF/FGFR Pathway: Fibroblast Growth Factor (FGF) is crucial for endothelial cell proliferation, migration, and differentiation . FGFR activation stimulates multiple processes in angiogenesis, particularly wound healing . Therapeutic Implication : Blocking FGFR helps combat resistance to VEGF-targeted therapies.

15. Signaling Pathways Angiopoietins/Tie Receptor Pathway : Ang-1 and Ang-2 regulate vessel stability and maturation . Tie-2 Receptor : Mediates effects of angiopoietins, balancing between vessel growth and regression . Therapeutic Targeting: Ang-2 inhibitors can prevent vessel destabilization and abnormal angiogenesis . HGF/c-Met Pathway : Hepatocyte Growth Factor (HGF) stimulates angiogenesis via the c-Met receptor . Role : Involved in tissue regeneration and promoting tumour invasiveness . Therapeutic Importance: c-Met inhibitors block angiogenesis, preventing tumour metastasis .

16. Signaling Pathways Notch/Delta-like Ligand (Dll) Pathway : Regulates sprouting angiogenesis and vascular remodelling. Dll-4 is crucial for controlling endothelial cell behaviour during vessel formation. Clinical Significance: Notch pathway inhibitors promote excessive, non-functional vessel sprouting, making it a potential target for therapy. Ephrins/EphR Pathway : EphrinB2/EphB4 interaction drives sprouting and branching of vessels. Role : Regulates arteriovenous formation and vascular maturation. Therapeutic Impact: Modulating Ephrin signalling can control aberrant vessel formation in tumors.

17. Angiogenesis in Cancer Angiogenesis is significant for tumor growth as it provides essential nutrient supply. New blood vessels facilitate waste removal from rapidly growing tumors. Early induction of angiogenesis occurs during the premalignant phase of cancer. Tumors stimulate angiogenic factors to promote vessel formation. Pathological features include aberrant vessel structures that are often irregular and leaky. Inefficient perfusion from these abnormal vessels can lead to tumor progression.

18. Anti-angiogenic Therapy Concept : Anti-angiogenic therapy seeks to inhibit blood vessel formation in tumors, thus "starving" the cancer cells of nutrients and oxygen. Therapeutic Strategies include: Monoclonal Antibodies (mAbs): These target VEGF or its receptors . Bevacizumab (Avastin®): Binds to VEGF-A, preventing its interaction with VEGFR-2, thus inhibiting angiogenesis ​ Tyrosine Kinase Inhibitors (TKIs): These small molecules block intracellular signalling from growth factor receptors involved in angiogenesis . Sorafenib (Nexavar®): Inhibits VEGFR, PDGFR, and other kinases, hindering tumour growth and vascularization ​. Endogenous Inhibitors: Molecules like angiostatin and endostatin are naturally occurring proteins that inhibit angiogenesis. For instance, endostatin blocks endothelial cell proliferation and induces vessel regression

19. Anti-Cancer Drugs Targeting Angiogenesis Bevacizumab (Avastin ®): Mechanism : Bevacizumab is a monoclonal antibody targeting VEGF-A. It neutralizes VEGF, preventing it from binding to VEGFR, thereby inhibiting endothelial cell proliferation and new blood vessel formation in tumors . Indications : Used in colorectal cancer (CRC), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), ovarian cancer, and glioblastoma . Therapeutic Effect: Demonstrates increased progression-free survival (PFS) and overall survival (OS) when combined with chemotherapy . Aflibercept (Eylea ®): Mechanism : A recombinant fusion protein acting as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF). It binds these factors, inhibiting their interactions with VEGFR, leading to reduced angiogenesis. Indications : Primarily used for neovascular diseases like age-related macular degeneration (AMD) and diabetic macular edema (DME). An oncology variant, Ziv-aflibercept, is used in metastatic colorectal cancer (CRC) .

20. Illustration

21. Future directions in Angiogenesis Research Targeting VEGF/VEGFR Pathway : The VEGF signalling axis remains the most exploited target in anti-angiogenesis therapy. Agents like bevacizumab, aflibercept, and ramucirumab effectively inhibit VEGF signalling to control tumor angiogenesis . Multi-Targeted Kinase Inhibitors (TKIs): These drugs, such as lenvatinib and sorafenib, inhibit multiple angiogenic pathways, reducing the likelihood of resistance by blocking compensatory mechanisms . Combination Therapy : Combining anti-angiogenic drugs with chemotherapy, immunotherapy, or other targeted agents (e.g., immune checkpoint inhibitors) can synergize to improve therapeutic outcomes. Biomarker Development : Research is focused on identifying biomarkers that predict patient response to anti-angiogenic therapy .

22. Conclusion Angiogenesis is fundamental to cancer progression, and anti-angiogenic therapy remains a key strategy in oncology. However, challenges like drug resistance and side effects demand continued research into combination therapies and novel angiogenesis inhibitors. A mix of pro-angiogenic and anti-angiogenic factors controls how things work. Targeting angiogenesis offers both challenges and opportunities for cancer treatment. Understanding the nuances of angiogenic regulation is essential for effective therapies. Future research will focus on developing innovative anti-angiogenic strategies. Collaborative efforts across disciplines will enhance the understanding and treatment of cancer.

23. References Cell signal. (2024). Angiogenesis. https://www.cellsignal.com/pathways/angiogenesis-pathway Kasherman , L., Siu, D. H. W., Woodford, R., & Harris, C. A. (2022). Angiogenesis inhibitors and immunomodulation in renal cell cancers: the past, present, and future. Cancers, 14(6), 1406. https://doi.org/10.3390/cancers14061406 Saman, H., Raza, S. S., Uddin, S., & Rasul, K. (2020). Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers, 12(5), 1172. doi:  10.3390/cancers12051172 Liu, Z.-L., Chen, H.-H., Zheng, L.-L., Sun, L.-P., & Shi, L. (2023). Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduction and Targeted Therapy, 8(198). https:// doi.org/10.1038/s41392-023-01460-1 Ferrara , N., & Kerbel, R. S. (2005). Angiogenesis as a therapeutic target. Nature, 438(7070), 967–974 . Carmeliet , P., & Jain, R. K. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature, 473(7347), 298–307 . Apte , R. S., Chen, D. S., & Ferrara, N. (2019). VEGF in signaling and disease: Beyond discovery and development. Cell, 176(6), 1248–1264.