Tumor pathogenesis. 陈玮 副教授 Email ： [email protected] 个人主页： http://mypage.zju.edu.cn/566 8888. Tumor pathogenesis Oncogenes Tumor suppressor genes Invasion and Metastasis. Introduction.
colon tumor progression
(~ 40-50 %)
(~ 60 %)
(~ 90 %)
(~ 50-70 %)
The precise contribution of hypomethylation to tumor progression remains unclear; some evidence suggests that it creates chromosomal instability.
Usually, a single oncogene is not enough to turn a normal cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.
Figure 2. Intracellular Signaling Networks Regulate the Operations of the Cancer Cell. An elaborate integrated circuit operates within normal cells and is reprogrammed to regulate hallmark capabilities within cancer cells. Separate subcircuits, depicted here in differently colored fields, are specialized to orchestrate the various capabilities. At one level, this depiction is simplistic, as there is considerable crosstalk between such subcircuits. In addition, because each cancer cell is exposed to a complex mixture of signals from its microenvironment, each of these subcircuits is connected with signals originating from other cells in the tumor microenvironment, as outlined in Figure 5. (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646)
An oncogene is a gene that when mutated or expressed at abnormally-high levels contributes to converting a normal cell into a cancer cell.
--- proto-oncogene （proto-onc）：in normal physiologic version
--- Oncogene：altered in cancer
cell growth, proliferation and differentiation:
Neoplasm Translocation Proto-oncogene
Burkitt lymphoma t(8;14) 80% of cases c-myc1
t(8;22) 15% of cases
t(2;8) 5% of cases
Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2
Acute lymphocytic t(9;22) 10-15% of cases bcr-abl2
1c-myc is translocated to the IgG locus, which results in its activated expression
2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase
Oncogene Amplification Source of tumor
c-myc ~20-fold leukemia and lung carcinoma
N-myc 5-1,000-fold neuroblastoma
L-myc 10-20-fold small-cell lung cancer
c-abl ~5-fold chronic myeloid leukemia
c-myb 5-10-fold acute myeloid leukemia
c-erbB ~30-fold epidermoid carcinoma
K-ras 4-20-fold colon carcinoma
30-60-fold adrenocortical carcinoma
Ras relays signals by acting as a switch
genes that sustain loss-of-function mutations in the development of cancer
Transcriptional factor: p53, WT1,
Direct transcription regulator: Rb, APC
Inhibitor of cell cylcle kinase: p16INK4A, p19ARF,
Cell structural components: NF2
Potential mediator of mRNA processing: VHL
Components involved in DNA repair: MSH2, MLH1, BRCA1, p53
Disorders in which gene is affected
Gene (locus) Function Familial Sporadic
DCC (18q) cell surface unknown colorectal
WT1 (11p) transcription Wilm’s tumor lung cancer
Rb1 (13q) transcription retinoblastoma small-cell lung
p53 (17p) transcription Li-Fraumeni breast, colon,
syndrome & lung cancer
BRCA1(17q) transcriptional breast cancer breast/ovarian
BRCA2 (13q) regulator/DNA repair
Rb inactivation by
KNUDSON TWO HIT HYPOTHESIS IN SPORADIC CASES
Inactivation of a tumor suppressor gene requires two somatic mutations.
Function as gatekeeper
antagonists in lipid signaling
Backman et al.
1.Loss of cell-to cell cohesive forces
2. Secretion of ECM-degrading enzymes
3. Active Locomotion
4. Tumor angiogenesis
5. Metastasis-related genes
Detachment of tumor cells from each other
Attachments of tumor cells to matrix components
Migration of tumor cells
5. Metastasis-enhancing Genes:Oncogenes,CD44, Integrinβ1, CEA, MMP2, u-PA, etc
expression ↓ in tumor
1. Structure: Heterodimeric proteins consisting of two non-covalently bound polypeptides ( and chains).
2. Components of integrin family
1: VLA (very late appearing antigen)
2: LFA-1 (lymphocyte function associated antigen-1); ligand: ICAM-1
3. ligands: the component of ECM including fibronectin（纤维黏连蛋白，FN）、vitronectin（玻璃黏连蛋白，VN）、laminin（层黏连蛋白，LM）。
Transmembrane glycoproteins, with a number of extracellular domains homologous to (CCP). The extracellular region also contains a domain related to the EGF receptor and a distal C type lectin-like domain.
2. Members of selectin family L-selectin: leukocytes P-selectin: platelets and megakaryocytes E-selectin: activated endothelia
3. Ligand: carbohydrates, such as CD15s (sialyl-Lewisx)
TIMPs play a key role in maintaining the balance between ECM deposition and its degradation by binding tightly to and regulating MMP actions
Four isoforms: TIMP 1-4
Tumor angiogenesis factors (TAFs)：angiogenin, etc Inhibitors：angiostatin, etc Models of Tumour Angiogenesis
Modified from JNCI 2000; 92:1717
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.
Angiogenesis is a ubiquitous and early event that is necessary for and promotes metastatic dissemination.
Invasion and angiogenesis use the same signal transduction programs and gene expression cassettes.
Circulating tumor cells can be detected in patients who do not develop overt metastatic disease.
Metastases may be as susceptible to anti- cancer therapy as their primary tumors?
Figure 4. The Cells of the Tumor Microenvironment.
(Upper) An assemblage of distinct cell types constitutes most solid tumors. Both the parenchyma and stroma of tumors contain distinct cell types and subtypes that collectively enable tumor growth and progression. Notably, the immune inflammatory cells present in tumors can include both tumor-promoting as well as tumor-killing subclasses.
(Lower) The distinctive microenvironments of tumors. The multiple stromal cell types create a succession of tumor
microenvironments that change as tumors invade normal tissue and thereafter seed and colonize distant tissues.
The abundance, histologic organization, and phenotypic characteristics of the stromal cell types, as well as of the
extracellular matrix (hatched background), evolve during progression, thereby enabling primary, invasive, and then metastatic growth.
Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target each of the
enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks.
(Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646).