Cancer as a Neural Circuit Disease

# The Hallmarks of Cancer, Part II: adaptation, invasion, and evolution *Evidence guide: Hallmark capabilities, enabling characteristics, and proposed new dimensions remain different categories in the audited framework.* Hallmark six: activating invasion and metastasis. Many cancers begin in an epithelium, tightly attached cells on a basement membrane. To invade, cancer cells loosen these attachments, remodel the surrounding matrix, and migrate, sometimes using a developmental program called the epithelial-to-mesenchymal transition. Metastasis is a multistep cascade. Local invasion. Intravasation, entering a blood or lymph vessel. Survival in the circulation. Extravasation, exiting at a distant site. And colonization, growing into a new tumor in a foreign tissue. Primary brain tumors such as gliomas are different. They very rarely spread outside the central nervous system. Their danger is diffuse invasion: single cells migrate far into the surrounding brain, so there is no clean edge for a surgeon to remove. Hallmark seven: deregulating cellular metabolism, which the 2022 paper calls reprogramming cellular metabolism. A dividing cell must build a whole new cell: membranes, proteins, and DNA. It needs raw materials, not just energy. Nearly a century ago, Otto Warburg noticed that many tumors take up lots of glucose and turn much of it into lactate, even with oxygen available. This is the Warburg effect, or aerobic glycolysis: an inefficient way to make ATP, but one that can help supply building blocks. Careful: the Warburg effect does not mean cancer cells stop using mitochondria. In most tumors, mitochondria stay active and necessary, supplying energy and building blocks. Metabolism is also flexible: cells shift between fuels, such as glucose, glutamine, and fats. Hallmark eight: avoiding immune destruction. Cells display fragments of their proteins on MHC molecules. Cytotoxic CD8 T cells inspect these fragments, and an abnormal fragment, such as one from a mutated protein, can mark a cell for killing. Natural killer cells add a second check: they can kill cells that stop displaying MHC. Tumors that grow have often escaped. Some stop displaying antigens. Others raise checkpoint signals such as PD-L1, which engage PD-1 on T cells and switch them off. Many recruit suppressive cells, like regulatory T cells, and immune pressure selects for cells the immune system cannot see. Checkpoint-blocking drugs release these brakes, but only some patients respond. Hallmark nine, proposed in 2022: unlocking phenotypic plasticity. Normal cells commit to an identity as they differentiate. Cancer cells can loosen that commitment: dedifferentiating toward a progenitor-like state, adopting stem-like properties, or shifting between programs in response to their environment. Beneath the hallmarks sit enabling characteristics, which help cells acquire the capabilities. Genome instability and mutation generates variation faster, fueling evolution. In tumor-promoting inflammation, immune signals meant to heal wounds supply growth and survival factors. But inflammation can also attack tumors; it is not always tumor-promoting. In 2022, Hanahan proposed further dimensions. Nonmutational epigenetic reprogramming, changing gene regulation without new DNA mutations, was proposed as an enabling characteristic, as were polymorphic microbiomes: microbes can influence some cancers and therapy responses, though relevance varies by tumor type. And senescent cells, whose secretions reshape nearby tissue, were proposed as part of the tumor microenvironment. Sources: [valastyan2011](https://doi.org/10.1016/j.cell.2011.09.024), [lun2011](https://doi.org/10.1007/s11060-011-0575-8), [cuddapah2014](https://doi.org/10.1038/nrn3765), [hw2011](https://doi.org/10.1016/j.cell.2011.02.013), [h2022](https://doi.org/10.1158/2159-8290.CD-21-1059), [vanderheiden2009](https://doi.org/10.1126/science.1160809), [vasan2020](https://doi.org/10.1016/j.cmet.2020.06.019), [schreiber2011](https://doi.org/10.1126/science.1203486), [ribas2018](https://doi.org/10.1126/science.aar4060), [hm2023](https://pmc.ncbi.nlm.nih.gov/articles/PMC10202656/), [grivennikov2010](https://doi.org/10.1016/j.cell.2010.01.025), [gopalakrishnan2018](https://doi.org/10.1126/science.aan4236), [coppe2008](https://doi.org/10.1371/journal.pbio.0060301).