Hallmarks of Cancer - Classical vs Metabolic approach
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Transcript of Hallmarks of Cancer - Classical vs Metabolic approach
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