The document summarizes the "Hallmarks of Cancer" proposed by Douglas Hanahan and Robert Weinberg in 2000. It identified six common traits or hallmarks that allow normal cells to transform into cancer cells: (1) self-sufficiency in growth signals, (2) insensitivity to anti-growth signals, (3) evading apoptosis, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) tissue invasion and metastasis. In 2011, Hanahan proposed four additional hallmarks: deregulated metabolism, immune evasion, severe chromosomal abnormalities, and chronic inflammation inducing cancer. The document discusses evidence that a metabolic approach may provide further insights into understanding cancer.

1. Hallmarks of Cancer
The fingerprints of a malevolent killer
Sreepadmanabh M
IISER Bhopal

2. The Logic
• the complexity of cancer can be reduced to a small number of underlying
principles
• all cancers share six common traits that govern the transformation of normal
cells to cancer (malignant or tumor) cells
• Cancer cells have defects in the control mechanisms that govern how often
they divide, and in the feedback systems that regulate these control
mechanisms

3. The “Han-berg” Effort
• Douglas Hanahan and Robert Weinberg published "The Hallmarks of
Cancer“ in the journal Cell in January 2000
• the paper has been referenced over 15,000 times by other research
papers, and was downloaded 20,000 times a year between 2004 and
2007 . As of March 2011, it was Cell's most cited article .

5. Self-sufficiency in growth signals
• Cancer cells do not need stimulation from external signals to multiply
• autocrine signaling ( self signaling) - by permanently activating the
signalling pathways or by destroying 'off switches' (negative feedback)

6. Insensitivity to anti-growth signals
• tumor suppressor genes
• Cancer cells do not have contact inhibition
• tumour suppressor proteins are altered so that they don't effectively
prevent cell division

8. Evading Apoptosis
• altering the mechanisms that detect the damage or abnormalities
• defects in the downstream signalling itself, or the proteins involved in
apoptosis

11. Limitless Replicative Potential
• Hayflick limit – 60 to 70 doublings before senescence
• 85% of cancers upregulate telomerase to extend their telomeres and
the remaining 15% use a method called the Alternative Lengthening
of Telomeres
• Telomerase keeps telomeres above the critical point

13. Sustained Angiogenesis
• continual supply of oxygen and other nutrients
• production of new vasculature by activating the 'angiogenic switch‘

15. Metastases
• Cancer cells break away from their site or organ of origin to invade
surrounding tissue and spread
• dictates whether the tumor is benign or malignant
• EMT – MET Transitions occur
• Starts with normal invasion , then enters bloodstream

17. The Hallmarks
• (1) Self-sufficiency in growth signals
• (2) Insensitivity to anti-growth signals
• (3) Evading apoptosis
• (4) Limitless replicative potential
• (5) Sustained angiogenesis
• (6) Tissue invasion and metastasis

18. Warburg’s Ghost
• Proposed by Nobel laureate Otto Heinrich Warburg in 1924
• the driver of tumorigenesis is an insufficient cellular respiration caused by
“insult” to mitochondria
• cancer cells exhibit glucose fermentation even when enough oxygen is present
to properly respire
• Reverse Warburg – tumor associated fibroblasts
• Inverse Warburg – neuronal loss – Alzheimer's ,Parkinsons

20. A small addition
In 2011 , Hanahan proposed 4 new hallmarks :
• Deregulated metabolism viz. Warburg
• Evading the immune system
• severe chromosomal abnormalities, which worsen as the disease progresses
• local chronic inflammation induces many types of cancer by DNA damage

22. Inklings of a different reality
• Evidences for metabolic changes
• Warburg effect and Reverse Warburg effect
• Success in diagnostic and screening measures relying on metabolic alterations
• Formulation of “Hallmarks of Cancer” using a metabolic approach based on
extensive research affirmation

23. A Metabolic Logic
• Cancer cells exhibit increased ability to obtain metabolites
• Preferential assignment of key metabolites to pathways required to
sustain tumorigenesis
• Alterations in local microenvironment and differentiation of cancer
cells themselves

24. A New March
• Exponentially increasing research into metabolic links to tumor
progression
• Synthesis and test runs of bio-markers and diagnostic tests based on
new logic
• Re-phrasing of hallmarks of cancer