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Cell
Signaling in
Cancer
NGUYEN Phuong Nga, PhD
“Advanced Cellular Biology”
Course– Dr Trang Huyen
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Dysregulated signaling in cancer
Douglas Hanahan and Robert A.
Weinberg
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Key signaling pathways that
drive cancer cell proliferation
• Ras/Raf/MEK,
• PI3K/Akt/mTor,
• Wnt/β-catenin
Representative oncogenes
ABL1, Abelson murine leukemia viral oncogene homolog 1; AKT/PKB, AKT/Protein Kinase B; BRAF, v-raf murine
sarcoma viral oncogene homolog B; CCND1, Cyclin D1; MYC, v-myc avian myelocytomatosis viral oncogene
homolog; EGFR, epidermal growth factor receptor; HER2, human diaminobenzidine epidermal growth factor receptor
2; KRAS, Kirsten rat sarcoma viral oncogene homolog; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase,
catalytic subunit alpha; SRC, SRC proto-oncogene, non-receptor tyrosine kinase
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Common pathways associated
with tumorigenesis
• increase in growth factor production
by the tumor
• increase in growth factor receptors on
the surface of malignant cells
• alteration of the structure of receptors
in transformed cells
• inappropriate response of cancerous
cells to the growth factors
from the tumor microenvironment
• dysregulation of downstream
signaling (mutation of downstream
proteins)
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• K-Ras,
Mutated Ras in cancer cell • H-Ras
• N-Ras
Frequency of known driver mutations identified in
adenocarcinoma of the lung and its target therapy
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[Link]
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K-Ras
N-Ras
B-Raf (V600E)
[Link]
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PI3K/Akt/mTOR signaling pathway
Class I phosphatidylinositol 3-kinase (PI3K)
intracellular interactions PIK3CA
mutations
• Breast
• Endometrial
• Urinary tract
• Cervical
• Skin
• Ovarian
PIK3R1
• Stomach
• Biliary tract
mutations
• Upper respiratory tract
• •Endometrial
Small intestine
• •Colorectal
Esophageal
• Cervical
• Upper respiratory tract
• Central nervous system
• Meningeal
• Breast
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Phosphatase and tensin homolog (PTEN)
C D
[Link]
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Activation of the Akt pathway affects a wide
range of vital cellular functions.
AKT isoforms and their somatic mutations in breast cancer
Human
pleckstrin homology catalytic domain regulatory domain
cancers with (PH) domain
Akt
mutations
• Meningeal
• Breast
• Endometrial
• Urinary tract
• Thyroid
• Skin
• Lung
• Ovarian
• Hematopoietic
and lymphoid
• Renal
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PI3K-Akt pathway regulates migration
2 2
2 2
2
2
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Wnt/β-catenin signaling in normal cell
βTrCP
Adenomatous polyposis coli (APC)
Dysregulation of Wnt/β-catenin pathway in cancer
- APC is a tumor suppressor
- APC germline mutations
lead to the loss or
reduction of APC protein,
which is associated with
cancer of the large
intestine and rectum.
- APC Somatic mutations
are associated with
malignancies of the lung,
breast, colon, rectum, and
other organs.
doi: 10.1053/[Link].2011.12.0
01
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Mutation rates of Wnt
pathway components in
selected cancer
Function of Wnt/β-catenin signaling
in cancer of gastrointestinal tract
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Pharmaceutical modulators of Wnt signaling pathway
Axin
β-Catenin
GSK CK1
Β-TrCP
[Link]
Judy Campisi, 2015
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extrinsic pathway
intrinsic pathway
caspase 3
caspase 7
Fas-associated death domain (FADD);
apoptotic protease activating factor-1 (APAF- [Link]
1);
inhibitor of apoptosis proteins (IAPs) family
How do cancer cells
escape apoptosis?
caspase 3
caspase 7
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How do cancer cells escape apoptosis?
SASP Judy Campisi, 2015
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[Link]
EGF epithelial growth factor, FGFs fibroblast growth factors, BMPs bone
morphogenetic proteins, IL1 interleukin 1, IL6 interleukin 6, IL8 interleukin 8,
CCL2 C–C motif chemokine ligand 2, MMP2 matrix metallopeptidase 2, [Link]
MMP3 matrix metallopeptidase 3
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Cellular senescence
generates a
pro-tumorigenic
microenvironment
platelet-derived growth factor
(PDGF)], matrix-
metalloproteinases (MMPs),
extracellular vesicles (EVs). [Link]
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[Link]
Angiogenic signaling pathway and angiogenesis
[Link]
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Angiogenic signaling pathway
VEGF signaling pathways and their
role in the pathogenesis of MPE
Malignant pleural effusion (MPE) is a
severe medical condition, which can result
in breathlessness, pain, cachexia and
reduced physical activity.
Lung cancer is the most common cause of
MPE, accounting for ~1/3 of clinical cases.
HIF-1, hypoxia-inducible factor-1; IL, interleukin; JNK, c-jun NH2-terminal
kinase; MAPKs, mitogen-activated protein kinases; MPE, malignant pleural
effusion; NOS, nitric oxide synthases; PAS, pathway activation signature;
PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC,
phosphoinositide phospholipase C; VEGF, vascular endothelial growth factor;
[Link]
VEGFR, VEGF receptor.
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Inhibition of angiogenesis induced by VEGFR signaling pathway
[Link]
MicroRNAs in tumor angiogenesis
Wang W. et al., 2015
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Signaling pathways involved in DNA damage and genomic
instability
Rasoul Yahyapour et al., 2018
Thank you
for your
attention
- Hippocrates used the terms
carcinos and carcinoma to
describe non-ulcer forming
and ulcer-forming tumors. In
Greek this means a crab. CANCE
- Roman physician, Celsus
(28-50 BC) translated the R
Greek term into cancer, the
Latin word for crab.
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