Transcript Tumor suppressor genes(TSGs)

Tumor pathogenesis
Genetic and epigenetic alterations in
cancer
 Oncogenes
 Tumor Suppressor Genes
 Invasion and Metastasis
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Jimin Shao
[email protected]
Invasion and Metastasis
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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
 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.
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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.
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
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
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
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
5. Tumor angiogenesis factors (TAFs)：angiogenin, etc
Inhibitors：angiostatin, etc
Models of Tumour Angiogenesis
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.
5. Metastasis-enhancing genes:
Oncogenes,CD44, Integrinβ1, CEA, MMP2, u-PA, etc
Metastasis-suppressor genes:
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-avb3 (Vitaxin)
Blocks endothelial cell
avb3 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
B. Signal Inhibitors: Blockade of signals necessary for angiogenesis ,
invasion, and metastasis
Agent
Target
CAI
Calcium influx
Squalamine
Inhibits NHE-3
PI3K inhibitors
MAPK inhibitors
Activity
Inhibits adhesion, motility, angiogenesis
Anti-angiogenic
Inhibit motility, proliferation, promote
Inhibit invasion, proliferation
6. Cancer stem cells
•tumorigenesis,
•metastasis,
•drug resistance,
• relapse
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
[J Clin Invest. 2009;119(6):1420-8. doi: 10.1172/JCI39104]
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)
EMT Signaling Pathways
J. P. Thiery, H. Acloque, R. Y. Huang, M. A. Nieto, Cell 139, 871 (2009)
Cancer Cell Metastasis Cascade
Chaffer CL, Weinberg RA. A Perspective on Cancer Cell Metastasis. Science 331, 1559 (2011)
Molecularly Targeted Therapy
 Cancer therapies: Resection (Surgery) , Chemotherapy, Molecularly
Targeted Therapy, Radiotherapy, Biotherapy (immunotherapy, gene
therapy, etc), and Others.
 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.
Therapeutic Targeting of the Hallmarks of Cancer
(Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646).
Anticancer drug discovery