1. Neoplasia (2&3 of 6) Ali Al Khader, M.D. Faculty of Medicine
Al-Balqa’ Applied University

2. 6 main mechanisms in cancer
also: -reprogramming of energy metabolism
-evasion of immune system

3. Self-Sufficiency in Growth Signals
Growth factors
Growth factor receptors and non-receptor tyrosine kinases
Downstream signal-transducing proteins
Nuclear transcription factors
Cyclins and cyclin-dependent kinases

4. Growth factors
The ability of neoplastic cells to synthesize the same growth factors to which they are responsive
…glioblastomas and PDGF
…many sarcomas and TGF-alpha
Sending signals to activate normal cells in surrounding stroma to secrete growth factors

5. Growth factor receptors and non-receptor tyrosine kinases
Several oncogenes result from mutation and overexpression of growth factor receptors
EGF receptor family
…ERBB1: -squamous cell carcinoma of lung
-glioblastoma
-epithelial tumors of the head and neck
…ERBB2 (HER2/NEU)…breast cancer
…also adenocarcinoma of -lung
-ovary
-salivary gland

6. Downstream signal-transducing proteins
RAS protein
…the most commonly mutated proto-oncogene
…especially in colon and pancreatic adenocarcinoma
…inactive when bound to GDP
activated by growth factors GDP is replaced by GTP
This activation is transient due to GTPase
GTPase-activating proteins (GAPs) GTPase activity

7. RAS protein and its downstream molecules, cont’d
>60% of melanomas

8. Downstream signal-transducing proteins
ABL protein
…a non-receptor tyrosine kinase
…in chronic myelogenous leukemias and certain acute leukemias:
a part of ABL gene is translocated from chromosome 9 to chromosome 22 (BCR gene)
a hybrid protein (BCR-ABL) is formed
…Gleevec (imatinib mesylate)???

9. Nuclear transcription factors
The ultimate consequence of signaling through oncoproteins such as RAS or ABL is stimulation of nuclear transcription factors
Examples of oncoproteins that are transcription factors:
MYC, MYB, JUN, FOS, and REL
drive the expression of growth promoting genes
The most common of these
…activates CDKs and inhibits CDKIs
…aerobic glycolysis and glutamine utilization
…t(8;14) in Burkitt lymphoma

10. Cyclins and cyclin-dependent kinases

11. Insensitivity to growth inhibitory signals
Tumor suppressor genes… proliferation/growth cycle
RB gene:
…mutated in sporadic and familial retinoblastoma cases
…60% of retinoblastoma cases are sporadic
…Knudson, in 1974: two-hit hypothesis…= the 2 alleles of RB gene must be inactivated
…in familial retinoblastoma, one allele is deficient (germline) and the other will be somatically mutated
…the inheritance of this susceptibility is: autosomal dominant

12. RB gene, cont’d
Hypophosphorylated Rb…complex with the E2F transcription factors
When Rb is phosphorylated by the cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 complexes
CDKI inactivate cyclin-CDK complexes
E2F is released…activates genes of S phase

13. Insensitivity to growth inhibitory signals, cont’d
TP53 gene:
…activation of temporary cell cycle arrest (termed quiescence)
…induction of permanent cell cycle arrest (termed senescence)
…activation of apoptosis and DNA repair
…MDM2 induces p53 degradation
…ATM release p53 from MDM2
…p CDKN1A (p21) transcription
…p53 activates DNA repair genes
…p53 activates pro-apoptotic genes
a CDKI that inhibits phosphorylation of RB by cyclin-CDK complexes

14. Insensitivity to growth inhibitory signals, cont’d
Contact inhibition…by certain transmembrane proteins, e.g., E-cadherin
APC…a tumor suppressor gene mutated in FAP

15. Evasion of cell death Remember our previous discussion of apoptosis
BCL-2 activity in follicular lymphoma and t(14;18)

16. Limitless replicative potential
Remember our discussion about telomeres and cellular aging
Short telomeres are recognized as double-stranded DNA breaks
leading to cell cycle arrest by p53 and Rb
if their genes are mutated…progressive DNA damage with more and more proliferation…but this is not enough and we want also to maintain telomeres
Maintenance of telomeres is present in all types of cancers…mostly by telomerase activity

17. Development of sustained angiogenesis
Tumors cannot enlarge beyond 1 to 2 mm in diameter unless they are vascularized
Important in benign and malignant tumors
Neoangiogenesis or vasculogenesis
This tumor vasculature is abnormal
New vessels contributes in tumor growth…secretion of growth factors

18. Sustained angiogenesis, important molecules and mechanisms
VEGF
…Notch signaling pathway
Thrombospondin-1 (TSP-1) is anti-angiogenetic…induced by normal p53
Angiogenesis can be induced by: -tumor cells
-surrounding ..inflammatory cells
..stromal cells

19. Sustained angiogenesis, important molecules and mechanisms, cont’d
FGF-2…released from ECM by proteases
3 potent angiogenesis inhibitors:
-angiostatin
-endostatin
-vasculostatin
Hypoxia HIF-1 alpha production of VEGF
a transcription factor
inhibited by the tumor suppressor VHL…its mutation will cause???

20. Ability to invade and metastasize… invasion-metastasis cascade

21. 1st step E-cadherin function is disabled in all epithelial cancers
by proteases such as MMPs and urokinase plasminogen activator
…secreted from tumor or stromal/inflammatory cells
Changes in attachment of tumor cells to ECM proteins
locomotion is the final step of invasion
cleavage products of matrix components have chemotactic activity for tumor cells
They are tumor cell-derived cytokines

22. Most tumor cells circulate as single cells …others circulate as emboli
Many tumors metastasize to the organ that presents the
first capillary bed they encounter after entering the circulation.
In many cases, however, the natural pathways of drainage
do not readily explain the distribution of metastases
Tissue-specific homing is highly determined by:
-adhesion molecules
-chemokines and chemokine receptors
-the environment for colonization in that tissue…so there may be micrometastases without progression (dormancy)
Of the transcription factors important for metastases:
-SNAIL
-TWIST

23. Tumor cells live in a complex and everchanging milieu composed of ECM, growth factors, fibroblasts, and immune cells, with significant cross-talk among all the components.

24. Reprogramming energy metabolism
Warburg effect
…= aerobic glycolysis
…How can tumor cells divide rapidly but with less ATP???

25. Evasion of the immune system
Tumor cells can be recognized by the immune system as non-self and destroyed
Cell mediated mechanisms:
…Tumor antigens are presented on the cell surface by MHC class I molecules
…recognized by CD8+ CTLs
Tumor antigens include:
-products of mutated proto-oncogenes, tumor suppressor genes
-overexpressed proteins
-tumor antigens produced by oncogenic viruses
-oncofetal antigens
-altered glycolipids and glycoproteins
-cell type– specific differentiation antigens
Immunosuppressed patients have an increased risk for development of cancer
In immunocompetent patients, tumors may avoid the immune system by several mechanisms, including selective outgrowth of antigen-negative variants, loss or reduced expression of histocompatibility antigens, and immunosuppression mediated by secretion of factors (e.g., TGF-β) from the tumor

26. Thank You