Cancer as a Neural Circuit Disease

# What is cancer? *Evidence guide: Established cancer biology and evolutionary interpretation. Distinguish molecular routes, cell states, and acquired capabilities.* Cancer begins when a lineage of cells acquires changes that let it break these rules. It is not one disease: there are many types, differing in tissue of origin, genetics, and behavior. But they share a theme. Cancer is an evolutionary process inside the body, in which cells that escape control outcompete their neighbors. Most of these changes are somatic mutations: alterations in the DNA of body cells, acquired during life, from copying errors or from damage such as ultraviolet light or tobacco smoke. Inherited predisposition plays a role in a minority of cancers, estimated at up to about one in ten. Three classes of genes matter most. First, proto-oncogenes: normal genes that promote growth, such as genes for growth-factor receptors. An activating change, like a point mutation, extra copies, or a gene fusion, can lock the protein in the 'on' state. It is then called an oncogene. Think of a stuck accelerator. One altered copy is often enough. Second, tumor-suppressor genes: the brakes. Their proteins halt division, or trigger repair or death. Usually both copies must be disabled before the brake fails. This classic two-hit model was first inferred from retinoblastoma, a childhood eye cancer. Third, DNA-repair genes. Losing them does not drive growth directly, but mutations accumulate faster, so other changes become more likely. And not every change is a mutation. Epigenetic changes alter how DNA is packaged and read, for example silencing a tumor-suppressor gene, without changing its sequence. Now add evolution. Suppose one cell gains an advantage and divides a little more often. Its descendants form a clone. Within that clone, new variation appears, and a cell that gains a second advantage expands again. Repeated rounds of variation and selection produce a branching family tree. Different tumors take different routes. A typical tumor carries a handful of driver mutations, often estimated at two to eight, among many passenger mutations that do not contribute. Even two cancers of the same organ can carry different drivers, acquired in a different order. There is no single universal sequence. The result is tumor heterogeneity. Cells within one tumor can differ in their mutations, in which genes they transcribe, in how differentiated they are, in their metabolism, and in their sensitivity to drugs. A treatment that kills most cells can spare a resistant subclone, which then regrows. Not every tumor is cancer. A benign tumor grows, but does not invade nearby tissue or spread, though a benign tumor in the brain can still be dangerous. A malignant tumor invades. Cancer cells that travel and grow at distant sites form metastases, which keep the identity of their primary tumor: breast cancer that spreads to the lung is still breast cancer. Sources: [nci-genetics](https://www.cancer.gov/about-cancer/causes-prevention/genetics), [nowell1976](https://doi.org/10.1126/science.959840), [knudson1971](https://doi.org/10.1073/pnas.68.4.820), [kinzler1997](https://doi.org/10.1038/386761a0), [mcgranahan2017](https://doi.org/10.1016/j.cell.2017.01.018), [vogelstein2013](https://doi.org/10.1126/science.1235122), [hw2011](https://doi.org/10.1016/j.cell.2011.02.013).