Hallmarks of CancerThe fingerprints of a malevolent killer

Sreepadmanabh M

IISER Bhopal

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

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 .

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)

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

Evading Apoptosis

• altering the mechanisms that detect the damage or abnormalities

• defects in the downstream signalling itself, or the proteins involved in apoptosis

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

Sustained Angiogenesis

• continual supply of oxygen and other nutrients

• production of new vasculature by activating the 'angiogenic switch‘

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

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

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

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

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

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

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