Hallmarks of Cancer
Introduction
Cancer is a complex group of diseases characterized by uncontrolled cell growth and the ability
to invade surrounding tissues or spread to distant organs. Over decades of research, scientists
have identified a set of biological capabilities—known as the "hallmarks of cancer"—that are
commonly acquired during the development of human tumors. These hallmarks provide a
framework for understanding the underlying mechanisms that drive cancer progression and offer
insights into potential therapeutic targets.
Originally proposed by Douglas Hanahan and Robert Weinberg in 2000 and later updated in
2011, the hallmarks include features such as sustaining proliferative signaling, evading growth
suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and
activating invasion and metastasis. Additional emerging hallmarks and enabling characteristics,
such as genome instability and immune system evasion, further deepen our understanding of
tumor biology.
Together, these hallmarks represent the fundamental changes that normal cells undergo to
become malignant. By examining these traits, researchers and clinicians can better diagnose,
monitor, and treat various forms of cancer. The hallmark framework continues to evolve,
incorporating new discoveries and technologies, and remains a cornerstone in cancer biology and
therapy development.
,1. Sustaining Proliferative Signaling
What It Means:
In healthy tissue, cell growth and division are tightly regulated by complex signaling networks
that balance proliferation with cell death, differentiation, and quiescence. However, in cancer,
this balance is broken. Cancer cells acquire the ability to sustain chronic proliferation, meaning
they grow uncontrollably, ignoring normal signals that should tell them to stop.
How Normal Cells Work:
In non-cancerous cells:
Growth factor ligands (e.g., Epidermal Growth Factor, EGF) bind to cell surface
receptors.
This triggers tightly controlled signaling cascades like:
o RAS/RAF/MEK/ERK pathway (promotes growth and division)
o PI3K/AKT/mTOR pathway (promotes survival and growth)
Negative feedback mechanisms and tumor suppressor genes keep these pathways in
check.
How Cancer Cells Hijack This System:
Cancer cells bypass normal regulatory mechanisms and hijack signaling pathways to constantly
“press the gas pedal” on growth. They achieve this through multiple mechanisms:
A. Autocrine Signaling
Cancer cells produce their own growth factors to stimulate themselves.
Example: Some glioblastomas secrete PDGF (Platelet-Derived Growth Factor) and
simultaneously express PDGF receptors.
B. Paracrine Signaling Manipulation
Tumor cells manipulate neighboring stromal or immune cells to secrete growth-
promoting factors.
C. Overexpression of Growth Factor Receptors
Tumors may amplify growth factor receptor genes, leading to excessive signaling even
without external stimuli.
Example: Breast cancers overexpress HER2/neu (ERBB2).
D. Constitutive Activation of Receptors
Receptors become mutated to be permanently “on”.
Example: EGFR mutations in non-small cell lung cancer (NSCLC) make the receptor
active without needing growth factors.
E. Downstream Pathway Activation
Mutations in downstream signaling proteins like:
o RAS mutations in pancreatic, colorectal cancers
o BRAF V600E mutation in melanoma
o PI3K mutations in breast cancer
result in constant proliferative signals even if the receptor is inhibited.
Classic Examples in Human Cancers:
Cancer Type Proliferative Mechanism
Non-Small Cell Lung Cancer (NSCLC) EGFR mutations leading to receptor hyperactivation
, Cancer Type Proliferative Mechanism
Breast Cancer HER2 amplification
Melanoma BRAF V600E mutations
Colon Cancer KRAS mutations
Glioblastoma Autocrine PDGF loop
Therapeutic Approaches (Detailed):
1. Growth Factor Receptor Blockade
EGFR Inhibitors:
o Small Molecule TKIs: Erlotinib, Gefitinib, Afatinib (for lung cancer)
o Monoclonal Antibodies: Cetuximab (for colorectal cancer)
HER2 Inhibitors: Trastuzumab, Lapatinib (for HER2+ breast cancer)
2. Downstream Pathway Inhibitors
BRAF inhibitors (Vemurafenib for melanoma)
MEK inhibitors (Trametinib)
PI3K inhibitors (Alpelisib for PIK3CA-mutant breast cancer)
3. Combination Therapies
Targeting both receptors and downstream pathways can overcome resistance (e.g., EGFR
+ MEK inhibitors in resistant NSCLC).
4. New Frontiers:
Antibody-Drug Conjugates (ADCs) targeting overexpressed receptors
Bispecific antibodies (e.g., targeting EGFR and MET together)
Clinical Importance:
Predictive Biomarkers: Testing for EGFR, HER2, KRAS, BRAF mutations guides
targeted therapy.
Resistance Mechanisms: Cancer can develop resistance via secondary mutations (e.g.,
T790M in EGFR) or activating alternative pathways (e.g., MET amplification).
Impact on Survival: Targeted therapies against proliferative signals have revolutionized
cancer treatment, offering better efficacy and fewer side effects compared to traditional
chemotherapy.
Summary:
“Sustaining proliferative signaling” is a foundational feature of cancer biology. It
illustrates the clever biological adaptations tumors employ to maintain continuous growth
and proliferation. Understanding these mechanisms has directly led to the development of
precision oncology, where treatments are tailored to the tumor’s specific genetic
alterations, leading to more personalized and effective care.
2. Evading Growth Suppressors
What It Means:
Introduction
Cancer is a complex group of diseases characterized by uncontrolled cell growth and the ability
to invade surrounding tissues or spread to distant organs. Over decades of research, scientists
have identified a set of biological capabilities—known as the "hallmarks of cancer"—that are
commonly acquired during the development of human tumors. These hallmarks provide a
framework for understanding the underlying mechanisms that drive cancer progression and offer
insights into potential therapeutic targets.
Originally proposed by Douglas Hanahan and Robert Weinberg in 2000 and later updated in
2011, the hallmarks include features such as sustaining proliferative signaling, evading growth
suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and
activating invasion and metastasis. Additional emerging hallmarks and enabling characteristics,
such as genome instability and immune system evasion, further deepen our understanding of
tumor biology.
Together, these hallmarks represent the fundamental changes that normal cells undergo to
become malignant. By examining these traits, researchers and clinicians can better diagnose,
monitor, and treat various forms of cancer. The hallmark framework continues to evolve,
incorporating new discoveries and technologies, and remains a cornerstone in cancer biology and
therapy development.
,1. Sustaining Proliferative Signaling
What It Means:
In healthy tissue, cell growth and division are tightly regulated by complex signaling networks
that balance proliferation with cell death, differentiation, and quiescence. However, in cancer,
this balance is broken. Cancer cells acquire the ability to sustain chronic proliferation, meaning
they grow uncontrollably, ignoring normal signals that should tell them to stop.
How Normal Cells Work:
In non-cancerous cells:
Growth factor ligands (e.g., Epidermal Growth Factor, EGF) bind to cell surface
receptors.
This triggers tightly controlled signaling cascades like:
o RAS/RAF/MEK/ERK pathway (promotes growth and division)
o PI3K/AKT/mTOR pathway (promotes survival and growth)
Negative feedback mechanisms and tumor suppressor genes keep these pathways in
check.
How Cancer Cells Hijack This System:
Cancer cells bypass normal regulatory mechanisms and hijack signaling pathways to constantly
“press the gas pedal” on growth. They achieve this through multiple mechanisms:
A. Autocrine Signaling
Cancer cells produce their own growth factors to stimulate themselves.
Example: Some glioblastomas secrete PDGF (Platelet-Derived Growth Factor) and
simultaneously express PDGF receptors.
B. Paracrine Signaling Manipulation
Tumor cells manipulate neighboring stromal or immune cells to secrete growth-
promoting factors.
C. Overexpression of Growth Factor Receptors
Tumors may amplify growth factor receptor genes, leading to excessive signaling even
without external stimuli.
Example: Breast cancers overexpress HER2/neu (ERBB2).
D. Constitutive Activation of Receptors
Receptors become mutated to be permanently “on”.
Example: EGFR mutations in non-small cell lung cancer (NSCLC) make the receptor
active without needing growth factors.
E. Downstream Pathway Activation
Mutations in downstream signaling proteins like:
o RAS mutations in pancreatic, colorectal cancers
o BRAF V600E mutation in melanoma
o PI3K mutations in breast cancer
result in constant proliferative signals even if the receptor is inhibited.
Classic Examples in Human Cancers:
Cancer Type Proliferative Mechanism
Non-Small Cell Lung Cancer (NSCLC) EGFR mutations leading to receptor hyperactivation
, Cancer Type Proliferative Mechanism
Breast Cancer HER2 amplification
Melanoma BRAF V600E mutations
Colon Cancer KRAS mutations
Glioblastoma Autocrine PDGF loop
Therapeutic Approaches (Detailed):
1. Growth Factor Receptor Blockade
EGFR Inhibitors:
o Small Molecule TKIs: Erlotinib, Gefitinib, Afatinib (for lung cancer)
o Monoclonal Antibodies: Cetuximab (for colorectal cancer)
HER2 Inhibitors: Trastuzumab, Lapatinib (for HER2+ breast cancer)
2. Downstream Pathway Inhibitors
BRAF inhibitors (Vemurafenib for melanoma)
MEK inhibitors (Trametinib)
PI3K inhibitors (Alpelisib for PIK3CA-mutant breast cancer)
3. Combination Therapies
Targeting both receptors and downstream pathways can overcome resistance (e.g., EGFR
+ MEK inhibitors in resistant NSCLC).
4. New Frontiers:
Antibody-Drug Conjugates (ADCs) targeting overexpressed receptors
Bispecific antibodies (e.g., targeting EGFR and MET together)
Clinical Importance:
Predictive Biomarkers: Testing for EGFR, HER2, KRAS, BRAF mutations guides
targeted therapy.
Resistance Mechanisms: Cancer can develop resistance via secondary mutations (e.g.,
T790M in EGFR) or activating alternative pathways (e.g., MET amplification).
Impact on Survival: Targeted therapies against proliferative signals have revolutionized
cancer treatment, offering better efficacy and fewer side effects compared to traditional
chemotherapy.
Summary:
“Sustaining proliferative signaling” is a foundational feature of cancer biology. It
illustrates the clever biological adaptations tumors employ to maintain continuous growth
and proliferation. Understanding these mechanisms has directly led to the development of
precision oncology, where treatments are tailored to the tumor’s specific genetic
alterations, leading to more personalized and effective care.
2. Evading Growth Suppressors
What It Means:
