Cancer as a Neural Circuit Disease

# The Hallmarks of Cancer, Part I: how tumors learn to grow *Evidence guide: Versioned Hallmarks framework. Eight core capabilities plus proposed plasticity form the nine teaching capabilities, not an official count.* In 2000, Douglas Hanahan and Robert Weinberg proposed organizing cancer’s complexity not by mutations but by capabilities: functions that cells acquire on the way to a malignant tumor, which they called the hallmarks of cancer. However varied the genetic routes, most cancers must acquire similar functions to grow and spread. The framework has been revised. The original paper listed six. In 2011, two emerging hallmarks and two enabling characteristics were added. In 2022, Hanahan moved the emerging hallmarks into the core, making eight, and proposed new dimensions, including one possible new hallmark. This course teaches nine capabilities: the eight core hallmarks plus that proposed one, as a teaching structure, not an official count. Two cautions. A hallmark is a capability, not a gene. One mutation can contribute to several hallmarks, and the same hallmark can be reached by different routes in different tumors. And not every cell in a tumor shows every hallmark equally. Hallmark one: sustaining proliferative signaling. In normal tissue, division is triggered by growth factors released by other cells. A growth factor binds a receptor on the cell surface, and a relay of proteins inside, a signaling cascade, carries the message to the nucleus. Because the supply of factor is limited, growth stays controlled. Hallmark two: evading growth suppressors. Cells also receive stop signals, and they have internal brakes. A key one is the RB protein. Before a cell commits to copying its DNA, RB holds back transcription factors called E2F, which switch on the copying machinery. Growth signals release this brake by phosphorylating RB. If RB is lost, the gate stays open. Hallmark three: resisting cell death. Apoptosis is regulated cellular suicide. A damaged or unneeded cell activates enzymes called caspases, dismantles itself into tidy fragments, and is cleared away by other cells, without spilling its contents. It is how the body removes cells whose DNA is badly damaged. Hallmark four: enabling replicative immortality. The ends of chromosomes are capped by repeated DNA sequences called telomeres. Because DNA copying cannot reach the very end, telomeres shorten with each division in most cells. When they become critically short, cells stop dividing for good, or die. This limits how many times most normal body cells can divide. Telomerase is an enzyme that rebuilds telomeres. It is active in germ cells and some stem cells, but kept very low in most body cells. Around ninety percent of cancers switch telomerase back on, and many of the rest use an alternative, recombination-based mechanism. Either way, the countdown stops. Hallmark five: inducing or accessing vasculature. Cells need oxygen and nutrients, and must remove waste, but these diffuse only a short distance from a blood vessel. A growing tumor outstrips its supply, and cells far from vessels become hypoxic, starved of oxygen. Many tumors respond with angiogenesis: they release factors such as VEGF that make nearby vessels sprout new branches toward them. Tumor vessels are often leaky and disorganized. In 2022, this hallmark was broadened to ‘inducing or accessing vasculature’, because some tumors instead co-opt existing vessels, growing along them. Sources: [hw2000](https://doi.org/10.1016/S0092-8674(00)81683-9), [hw2011](https://doi.org/10.1016/j.cell.2011.02.013), [h2022](https://doi.org/10.1158/2159-8290.CD-21-1059), [jafri2016](https://doi.org/10.1186/s13073-016-0324-x), [hanahanfolkman1996](https://doi.org/10.1016/S0092-8674(00)80108-7).