The pioneering paper on Hallmarks of Cancer by Hanahan and Weinberg was published in 2000, and addressed the hallmarks of cancer cells. These proposed hallmarks were said to dictate malignant growth
1) Cancer cells don't require external signal stimulation to grow. They either produce signals themselves (autocrine signalling), permanently activating signalling pathways, or destroying "off switches" preventing excessive growth (negative feedback). Also, cell division processes are deregulated in cancer, due to protein alteration, this increased cell division and growth within the tumour.
2) Tumour suppressor proteins are altered so they don't prevent cell division upon the cell developing severe abnormalities. Cancer cells also don't have contact inhibition (knowing when they have filled up a space), so will continue to grow after they've filled their surroundings.
3) Cancer cells don't undergo cell death, which they do by altering mechanisms that recognise abnormalities. It is proposed that cancer cells do this by altering the mechanisms that detect cellular damage or abnormalities, meaning that apoptosis cannot activate.
4) Where non-cancer cells die after a certain number of divisions or become unable to divide (senescence), cancer cells are able to grow indefinitely. A large reason for this is due to cancer cells manipulating telomerase to increase telomeres, the DNA at the end of the chromosomes that forms a barrier for replication. In mammalian cells, there is an intrinsic mechanism called the Hayflick limit, which limits the cells multiplications before it reaches its limit for senescence. This limit is overcome in cancer cells be disabling the pRB and p53 tumour suppressor proteins, allowing for the continuation of doubling and the emergence of immortalised cells.
5) Cancer cells kickstart angiogenesis to ensure they have a continual supply of oxygen and nutrients. They do this by reducing the production of factors that inhibit blood vessel production, and increasing the production of factors that promote blood vessel formation.
6) Cancer cells can break off from the original tumour, and spread to other tissues. They do this by invading local cells in the surrounding tissue, before travelling in the lymphatic or blood system to other tissues. This is a key hallmark of malignancy in cancer.
Later on, Hanahan proposed further emerging hallmarks and characteristics:
1) deregulated metabolism - where cancer cells upregulate glycolysis and lactic acid fermentation in the cytosol, preventing mitochondria from completing normal aerobic respiration. Cancer cells then convert pyruvate into more of the building blocks for cancer cells, rather than producing ATP.
2) evading the immune system - cancer cells appear to avoid interaction with the immune system in the body via a loss of interleukin-33.
3) genome instability - genetic mutations are most likely to be the thing that starts tumourigenesis
4) inflammation - chronic local inflammation could induce cancer. Inflammation leads to angiogenesis and more immune response.
Cancer is something that we are still learning about and developing our understanding, and these changing and defining hallmarks are definitely an example of this!