Epithelial ovarian cancer

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]

Possible genetic alteration in epithelial ovarian cancers
Protein Normal function Function in malignancy
Epidermal growth factor receptor (HER-1)[1][2]
  • Promotes cell proliferation
  • Opposes apoptosis
  • Regulates differentiation
  • Activating mutation
  • Increased cellular proliferation
  • Inhibition of apoptosis
Human Epidermal Growth Factor Receptor 2 (HER-2)[1][2]
  • Promotes cell prolifeartion
  • Inhibition of apoptosis
  • Regulates differentiation
  • Activating mutation
  • Increased cellular proliferation
  • Inhibition of apoptosis
Non-receptor tyrosine kinase Src[3][4] Involved in regulation of
  • Gene transcription
  • Angiogenesis
  • Cellular adhesion
  • Cellular proliferation
  • Activating mutation
  • Increased angiogenesis
  • Decreased cellular adhesion
  • Increased tumor metastasis
  • Increased cellular proliferation
CSF-1/fms[5][6][7]
  • Increased macrophage survival
  • Increased macrophage proliferation
  • Increased macrophage differentiation
  • Activating mutation
  • Stimulation of tumor cell proliferation
  • Increased angiogenesis
  • Promotes tumor invasion
  • Increased metastasis
  • Decreased anoikis
Insulin-like growth factor/receptor ILGF/ILGFR[8][9][10]
  • Promotes growth
  • Increased survival
  • Activating mutation
  • Increased proliferation
  • Enhanced survival
  • Suppression of cell cycle regulators
k-ras[11][12]
  • Cellular proliferation
  • Cell survival
  • Activating mutation
  • Increased proliferation
  • Enhanced survival
b-raf[13][14]
  • Cellular proliferation
  • Cellular differentiation
  • Activating mutation
  • Increased proliferation
  • Enhanced growth
TGF-β[15][16][17]
  • May function as a tumor suppressor and a promoter
  • Promotes growth arrest
  • Maintains cellular homeostasis
  • Increased proliferation
  • Decreased apoptosis
  • Epithelial-to-mesenchymal transition
  • Sustained angiogenesis
  • Evasion of immune surveillance
  • Metastasis
myc[18][19][20]
  • Derives cellular proliferation
  • Increased growth
  • Cell-cycle mediator
  • Inhibits apoptosis
  • Stem-cell renewal
  • Activating mutation
  • Increased proliferation
  • Decreased apoptosis
  • Increased metabolism in tumor cells
Cyclin D/Cdk4/6[21][22][23]
  • Cell-cycle mediator
  • Controls G1 length
  • Activating mutation
  • Decreased G1 length
  • Increased proliferation
  • Increased angiogenesis
Cyclin E/Cdk2[24][25][26]
  • Cellular proliferation
  • Cell-cycle mediator
  • Assembly of the pre-replication complex
  • Promotes G0 to cell cycle entry
  • Promotes G1 to S phase transition
  • Decreased apoptosis
  • Activating mutation
  • Increased cellular proliferation
  • Impaired apoptosis
  • Increased cellular survival
Cyclin B/Cdk1[27][28][29]
  • Cell-cycle mediator
  • promotes G2 to M phase transition
  • Activating mutation
  • Increased cellular proliferation
  • Promotes malignant transformation
p16[30][31][32]
  • Member of the INK4 family of CDK inhibitors
  • Inhibits Cyclin D/Cdk4/6
  • Decreased G1 to S phase transition
  • Lost or downregulated
  • Decreased G1 length
  • Increased proliferation
  • Increased angiogenesis
p27 (kip-1)[33][34][35]
  • Inhibitor of Cyclin E/Cdk2
  • Mediates cell cycle arrest
  • Decreased G1 to S phase transition
  • May act as oncogen and promote proliferation
  • Lost or dysregulated
  • Increase in cell proliferation
  • Impaired apoptosis
p21 (WAF-1)[36][37][38]
  • Inhibits cyclin-dependant kinases
  • Cell-cycle arrest
  • Decreased proliferation
  • Promotes cellular differentiation
  • May inhibit/promote apoptosis
  • May act as oncogen and promote proliferation
  • Lost or dysregulated
  • Increase in cell proliferation
  • Decreased cellular differentiation
  • Decreased apoptosis
  • Correlates positively
    • tumour grade
    • invasiveness
    • aggressiveness
NFκB[39][40][41]
  • A transcription factor involved in regulation of
    • immune response to inflammation
    • expression of cytokines, chemokines, and adhesion molecules
    • cell cycle
    • apoptosis
  • May function as a tumor suppressor and a promoter
  • Dysregulated
  • Increased angiogenesis
  • Enhanced tumor growth
  • Induces resistance to chemotherapy by acting as anti-apoptosis
NOEY(ARHI)[42][43][44][45]
  • Inhibits cell growth
  • Induces apoptosis
  • Inhibits tumor cells migration through chemotaxis and haptotaxis
  • Inactivating mutation
  • Enhanced tumor growth
  • Decreased apoptosis
  • Increased chances for metastasis
PIP3/Akt[46][47]
  • Akt is activated by PIP3 and plays a role in
    • regulation of cellular growth
    • cell cycle progression
    • regulation of glucose metabolism
    • genome stability
    • gene transcription
    • protein synthesis
    • neovascularization
    • promotes cell survival by blocking apoptosis
  • Activating mutations
  • Increased cellular proliferation
  • Increased tumor cells survival
  • Increased tumor cells migration
  • Increased tumor cells invasion
  • Chemotherapy resistance
  • Decreased apoptosis
  • May promote angiogenesis
PTEN[48][49][50]
  • Suppresses Akt and thus regulates cell cycle, cellular growth and apoptosis
  • Regulates self-renewal and differentiation of human stem cells
  • Regulates oocyte growth and follicular activation
  • Regulates chemotaxis of neutrophils
  • Inhibit cell invasion and migration
  • Deletion or inactivating mutation
  • Increased cellular proliferation
  • Increased tumor cells survival
  • Increased tumor cells migration
  • Increased tumor cells invasion
  • Decreased apoptosis
p53[51][52][53]
  • A transcription factor that
    • regulates cell cycle
    • promotes DNA damage repair
    • promotes apoptosis
    • maintains genomic integrity
  • Loss results in
    • DNA damage and carcinogenesis
    • increased tumor cell growth and survival
    • increased metastasis
    • decreased apoptosis
    • resistance to chemotherapy
BRCA1[54][55][56]
  • A tumor suppressor that mediates double stranded DNA repair through
    • homologous recombination pathway
    • non-homologous end joining pathway
  • Activates checkpoints in cell cycle
  • Maintains genomic integrity
  • Mutations are responsible for hereditary breast & ovarian tumors
  • Loss results in
    • DNA damage and carcinogenesis
    • increased tumor cell growth and survival
BRCA2[54][55][56]
  • A tumor suppressor that mediates double stranded DNA repair through
    • homologous recombination pathway
  • Maintains genomic integrity
  • Protects replication fork and replication fidelity
  • Mutations are responsible for hereditary breast & ovarian tumors
  • Loss results in
    • DNA damage and carcinogenesis
    • increased tumor cell growth and survival
  • Defects in maintenance the length of the nascent strand of DNA
MLH1/MSH2[57][58][59]
  • Tumor suppressors that
  • mediates DNA damage repair
  • maintains genomic integrity
  • possible regulation of cell cycle
  • Loss results in
    • DNA damage and carcinogenesis
    • increased survival
    • resistance to chemotherapy
    • chromosomal instability
    • microsatellite instability (MSI)
    • the cytosine phosphate guanine (CpG) island methylator phenotype (CIMP)
Fas ligand[60][61][62]
  • Binds to Fas receptor and induces apoptosis
  • Expressed mainly on T-lymphocytes
  • May induce apoptosis in cancer cells and virus infected cells
  • May also be involved in
    • liver regeneration following partial hepatectomy
    • neurite outgrowth
  • Most tumor cells are resistant to Fas-FasL mediated apoptosis
  • Tumor cells express FasL to induce apoptosis in cytotoxic lymphocytes
  • Promotes tumor cells survival
  • Enhances tumor cells invasion
  • Increased tumor cells migration
HLA-G[63][64][65]
  • Inhibits T-cell function through
    • inhibiting proliferation
    • causing cytotoxicity
    • inducing apoptosis
    • cytokine production in B lymphocytes
    • inhibiting differentiation
  • Inhibits proliferation and cytotoxicity of natural killer cells
  • Promotes angiogenesis
  • Inhibits chemotaxis
  • Promotes progression of cancer through evasion of immune response by
    • inhibiting T-cell functions by inducing apoptosis and decreased proliferation
    • inhibiting T-cell differentiation through various mechanisms
  • Inhibits proliferation and cytotoxicity of natural killer cells
  • Promotes angiogenesis
  • Inhibits chemotaxis of cytotoxic cells
hTERT[66][67][68]
  • Maintains telomeres length
  • Promotes replication
  • Up-regulated in majority of human cancers
  • Provides limitless replication ability to cancer cells
VEGF/VEGFR[69][70][71]
  • Stimulates angiogenesis through
    • increased endothelial cell survival
    • Increased endothelial cell proliferation
    • increased endothelial cell migration
  • Increases vascular permeability
  • May regulate fibroblasts in the stroma of tumors
  • May effect tumor stem cells
  • Promotes angiogenesis
  • Promotes tumor cells growth
  • May initiate carcinogenesis
  • Promotes invasion and metastasis of tumor cells
IL-8[72][73][74]
  • Chemokine produced to recruit leukocytes and myeloid-derived suppressor cells
  • Promotes epithelial-to-mesenchymal transition
  • Promotes infection resolution
  • Promotes angiogenesis
  • Promotes epithelial-to-mesenchymal transition in tumor cells
  • Promotes resistance to chemotherapy
  • Tumor progression through immunosuppressive and pro-tumorigenic immune cells
  • Promotes angiogenesis
  • Promotes invasion and metastasis
EphA2[75][76][77]
  • Promotes angiogenesis
  • Plays a key role in development of
    • Lens
    • Inner ear
    • Mammary glands
  • Promotes kidney repair following injury
  • Promotes bone remodeling bone remodeling
  • Over-expressed in ovarian epithelial cancer
  • Promotes tumor initiation
  • Promotes neo-vascularization
  • Promotes tumor invasion
  • Promotes metastasis
MMPs[78][79][80]
  • Proteases that degrade tissues, matrix and other proteins and play a role in
    • bone modeling and remodeling
    • mammary development
    • blood vessels remodeling
    • a variety of other tissues such as tracheal tube
  • Promotes inflammation through enzymatic activation
  • Over-expressed in ovarian epithelial cancer
  • Promotes tumor invasion through degradation of extra-cellular matrix
  • Promotes metastasis through degradation of extra-cellular matrix
  • May have a role in tumor initiation and angiogenesis
αvβ3[81][82][83]
  • One of the most important mediator of angiogenesis
  • promotes smooth muscle cells migration and proliferation
  • Promotes angiogenesis
  • Promotes survival
Focal adhesion kinase (FAK)[84][85][86]
  • Promotes endothelial cells migration
  • May play a role in integrin-dependent cell survival signal
  • Inhibits apoptosis
  • Enhances cell motility
  • Promotes angiogenesis
  • Promotes tumor cells survival
  • Inhibits apoptosis
  • Promotes tumor metastasis
E-cadherin

References

  1. ↑ 1.0 1.1 Wee P, Wang Z (May 2017). "Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways". Cancers (Basel). 9 (5). doi:10.3390/cancers9050052. PMC 5447962. PMID 28513565.
  2. ↑ 2.0 2.1 Iqbal N, Iqbal N (2014). "Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications". Mol Biol Int. 2014: 852748. doi:10.1155/2014/852748. PMC 4170925. PMID 25276427.
  3. ↑ Zan L, Wu H, Jiang J, Zhao S, Song Y, Teng G, Li H, Jia Y, Zhou M, Zhang X, Qi J, Wang J (July 2011). "Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema". Neurochem. Int. 58 (8): 872–9. doi:10.1016/j.neuint.2011.02.014. PMC 3100427. PMID 21334414.
  4. ↑ Reinecke JB, Katafiasz D, Naslavsky N, Caplan S (April 2014). "Regulation of Src trafficking and activation by the endocytic regulatory proteins MICAL-L1 and EHD1". J. Cell. Sci. 127 (Pt 8): 1684–98. doi:10.1242/jcs.133892. PMC 3986674. PMID 24481818.
  5. ↑ Saad AF, Hu W, Sood AK (December 2010). "Microenvironment and pathogenesis of epithelial ovarian cancer". Horm Cancer. 1 (6): 277–90. doi:10.1007/s12672-010-0054-2. PMC 3199131. PMID 21761359.
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