1. Tumor pathogenesis  Genetic and epigenetic alterations in cancer  Oncogenes  Tumor Suppressor Genes  Invasion and Metastasis Jimin Shao shaojimin@zju.edu.cn

2. Invasion and Metastasis  A hallmark of malignancy, occurs in four steps: Growth at primary site and angiogenesis Tumor cell invasion Lymphatic and hematogenous metastasis Growth at secondary site and angiogenesis

3.  Up to 70% of patients with invasive cancer have overt or occult metastases at diagnosis.  Acquisition of the invasive and metastatic phenotype is an early event in cancer progression.  Millions of tumor cells are shed daily into the circulation.  Less than 0.01% of circulating tumor cells successfully initiate a metastatic focus.  Circulating tumor cells can be detected in patients who do not develop overt metastatic disease.  Angiogenesis is a ubiquitous and early event that is necessary for and promotes metastatic dissemination.

4. Mechanisms involved in tumor cell invasion 1.Loss of cell-to cell cohesive forces: Decreased cellular adhesion 2. Secretion of ECM-degrading enzymes: Degradation of ECM 3. Active Locomotion: Abnormal or increased cellular motility 4. Protein kinases 5. Tumor angiogenesis 6. Metastasis-related genes 7. Cancer stem cell 8. EMT

6. 1. Loss of cell-to cell cohesive forces: Cell adhesion molecules (CAMs ）： 细胞粘附分子 : 介导细胞之间、或细胞与 ECM 之间的选择性粘附。 E-cadherin: Expression↓ Loss of cell-cell adhesion ， Increased cell motility Integrins ： Expression↓→↑ Immunoglobin superfamily ： NCAM, VCAM-1,CEA, DCC, etc Selectins CD44 variants

7. 2. Secretion of ECM-degrading enzymes  Matrix Metalloproteinases (MMPs) ：～ 20  Tissue inhibitors of metalloproteinases (TIMPs) ： ～ 4  Plasminogen Activators (PAs): urokinase-type (uPA) tissue-type (tPA)  PA inhibitors (PAIs): ～ 3

8. 3. Active Locomotion E- cadherin Growth factors and receptors, Autocrine motility factor (AMF), Autotaxin (ATX), Cytoskeletal proteins ECM components (laminin, LN, etc ） 4. Protein Kinases Rho GTPases FAK

9. 5. Tumor angiogenesis factors (TAFs) ： angiogenin, etc Inhibitors ： angiostatin, etc Models of Tumour Angiogenesis

10. Blocking Blood Supply to Tumors Many solid tumors are dependent on the growth of new blood and lymphatic vessels to grow and survive. In the past 10 years, the FDA has approved 10 antiangiogenic agents. The newest member of this growing class of therapeutics is ramucirumab (Cyramza). It was approved by the FDA for the treatment of metastatic gastric cancer and gastroesophageal junction adenocarcinoma in April 2014. Ramucirumab is also being tested in numerous clinical trials as a potential treatment for other types of cancer, such as NSCLC.

12. Metastasis-suppressor genes: 5. Metastasis-enhancing genes: Oncogenes,CD44, Integrinβ1, CEA, MMP2, u-PA, etc

13. Metastasis Therapeutic Targets and Agents A. Targeted Therapeutics Target Example Agents Effects Growth factors C225 (anti-EGFR) Block growth factor signaling Tyrphostins (anti-RTK) Cell adhesion Anti-  v  3 (Vitaxin) Blocks endothelial cell  v  3 peptidomimetics interaction with matrix may regulate MP activation Proteolysis MMPIs uPAR-I Blocks degradation of matrix, blocks activation of proteases, growth factors Motility Taxanes Blockade of microtubule cycling

14. B. Signal Inhibitors: Blockade of signals necessary for angiogenesis, invasion, and metastasis Agent Target Activity CAI Calcium influx Inhibits adhesion, motility, angiogenesis Squalamine Inhibits NHE-3 Anti-angiogenic PI3K inhibitors Inhibit motility, proliferation, promote MAPK inhibitors Inhibit invasion, proliferation

15. 6. Cancer stem cells tumorigenesis, metastasis, drug resistance, relapse

16. [J Clin Invest. 2009;119(6):1420-8. doi: 10.1172/JCI39104] 7.Epithelial-mesenchymal transition (EMT) EMT 有三种形式： I 型 EMT （上皮细胞 - 间质细胞转换） : 胚胎发育 ; 发育异常，畸形（先天性瓣膜性心脏病） II 型 EMT （上皮细胞 - 成纤维细胞转换） : 创伤修复，瘢痕形成 ; 不愈合，过度愈合（纤维化性疾病） III 型 EMT （肿瘤上皮 - 间质细胞转换） 肿瘤侵袭转移 ; 耐药，酸中毒抵抗，凋亡抵抗 ; 干细胞样特征

17. Epithelial-mesenchymal plasticity allows cancer cells to undergo functional adaptations during the invasion-metastasis cascade W. L. Tam, R. A. Weinberg, Nat Med 19, 1438 (Nov, 2013)

19. EMT Signaling Pathways J. P. Thiery, H. Acloque, R. Y. Huang, M. A. Nieto, Cell 139, 871 (2009)

20. Cancer Cell Metastasis Cascade Chaffer CL, Weinberg RA. A Perspective on Cancer Cell Metastasis. Science 331, 1559 (2011)

23.  Research is making it increasingly possible to link specific defects in the molecular machinery of cells to cancer development.  This knowledge is enabling the development of medicines that precisely target these alterations and block their ill effects.  The standard of care is transforming from a one-size-fits-all approach to personalized cancer medicine.  The number of molecularly targeted therapies approved by the FDA is increasing as our knowledge of cancer biology expands.  personalized cancer medicine or precision medicine, is still very much in early development, but it clearly represents the future of cancer care. Molecularly Targeted Therapy  Cancer therapies: Resection (Surgery), Chemotherapy, Molecularly Targeted Therapy, Radiotherapy, Biotherapy (immunotherapy, gene therapy, etc), and Others.

24. (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646). Therapeutic Targeting of the Hallmarks of Cancer

25. Anticancer drug discovery