Inflammation and cancer

One in four cancers worldwide traces back not to a genetic accident you were born with, or to a carcinogen you inhaled once, but to your own immune system trying to heal you. That is the number Mariko Murata puts on the table at the outset: infectious disease and chronic inflammation together account for approximately twenty-five percent of cancer-causing factors. So the question driving this lecture isn't just what cancer is. It's why the body's defense mechanism — the thing designed to protect you — becomes the thing that kills you. The infectious culprits Murata identifies are diverse on the surface but share a common effect inside tissue. Opisthorchis viverrini, a liver fluke, drives cholangiocarcinoma. Schistosoma haematobium, a parasitic worm, is linked to bladder cancer. Helicobacter pylori sits in the stomach and raises gastric cancer risk. Human papillomavirus targets the cervix. Epstein-Barr virus is associated with nasopharyngeal carcinoma. What these agents have in common isn't a shared mutation they introduce directly. It's that they all trigger persistent, localized inflammatory responses that never fully resolve. The inflammation becomes chronic. And chronic inflammation, it turns out, is molecularly catastrophic. Here's how. When immune cells flood into inflamed tissue, they unleash reactive oxygen species and reactive nitrogen species — known as ROS and RNS — as chemical weapons against the perceived threat. Enzymes called NADH oxidase and inducible nitric oxide synthase drive this production. Nitric oxide combines with superoxide to form peroxynitrite. Hydrogen peroxide reacts with iron in what's called the Fenton reaction to produce the hydroxyl radical. These are extraordinarily reactive molecules, and they don't discriminate. They hit everything nearby — including the DNA of perfectly healthy cells trying to go about their business. Two signature lesions emerge from this chemical assault. The first is 8-oxo-7,8-dihydro-2'-deoxyguanosine, or 8-oxodG — a chemically modified version of one of DNA's four bases that mispairs during replication and introduces mutations. The second is 8-nitroguanine, another modified base with similar mutagenic consequences. Murata's group found these lesions appearing in cancer and precancerous tissue across every one of the infection-linked cancers she studied. In patients with Opisthorchis viverrini-related cholangiocarcinoma, urinary 8-oxodG levels were significantly higher than in patients merely infested with the parasite, and higher still compared to healthy subjects. Critically, when patients infested with Opisthorchis viverrini received antiparasite therapy, their 8-oxodG levels dropped significantly within two months and reached healthy-subject levels within a year. These aren't random background mutations. They are the molecular fingerprint of inflammation — and they are reversible if you stop the inflammation in time. Now here is where it gets more alarming. Murata's work shows these DNA lesions don't accumulate uniformly across all tumor cells. In Opisthorchis viverrini-related cholangiocarcinoma, cells positive for stem-cell markers CD133 and Oct3/4 carried significantly higher levels of 8-oxodG than marker-negative cells — and those marker-positive cases had poorer prognoses. In Epstein-Barr virus-associated nasopharyngeal carcinoma, 8-nitroguanine was concentrated in cells positive for stemness markers CD44v6 and ALDH1A1. Cancer stem-like cells are the subpopulation within a tumor that can self-renew and regenerate the rest of the tumor — they're the cells that drive growth, metastasis, and treatment resistance. When Murata's team grew hydrogen-peroxide-resistant cholangiocytes by exposing a cell line to twenty-five micromolar hydrogen peroxide daily for more than two months, the resistant line's tolerance for hydrogen peroxide jumped from an IC50 of seventy-five micromolar to three hundred fifty micromolar, and the cells grew faster and expressed more antioxidant enzymes. Knocking down the tumor suppressor EBF1 in these models increased CD133 and Oct3/4 expression and enhanced cell migration. The implication is stark: if chronic inflammation preferentially damages the cells that can self-renew and repopulate a tumor, it explains why inflammation-related cancers so often present with aggressive clinical features. But DNA isn't the only casualty. Murata makes the case that reactive oxygen and nitrogen species also damage proteins and lipids, and that those protein lesions create a self-amplifying catastrophe. To identify which proteins carry oxidative damage in cancer tissue, her group used a technique called two-dimensional Oxyblot followed by matrix-assisted laser desorption ionization time of flight and time of flight mass spectrometry — think of it as molecular fingerprinting applied specifically to damaged proteins, separating them in two dimensions and then identifying each by mass. One of the proteins they found oxidatively damaged was transferrin, the molecule the body uses to shuttle iron safely through the bloodstream. Oxidized transferrin releases its iron. That free iron then drives Fenton reactions, generating still more hydroxyl radicals and still more reactive oxygen species. And here is the part that closes the trap: among the proteins vulnerable to oxidative damage are the cell's own antioxidant proteins — the very defenses meant to neutralize reactive oxygen species. When those are disabled, oxidative stress rises further. Inflammation generates reactive oxygen species, reactive oxygen species damage antioxidant proteins, antioxidant proteins fail, reactive oxygen species levels climb, and the cycle accelerates. Murata describes this explicitly as a vicious cycle, and it's the right word — each step in the loop makes the next iteration worse. Alongside this direct molecular damage, inflammation operates through a second, parallel channel: epigenetics. Epigenetic changes alter which genes are expressed without changing the DNA sequence itself. Murata identifies two mechanisms at work in inflamed tissue. The first is DNA methylation — specifically, the addition of chemical tags to regulatory regions called CpG islands in gene promoters, which silences the gene downstream. The second is microRNA dysregulation. MicroRNAs are short RNA molecules, eighteen to twenty-five nucleotides long, that post-transcriptionally suppress target genes. Both mechanisms can knock out tumor suppressor genes — the brakes on cell proliferation — without touching a single nucleotide in the gene's sequence. Murata's team investigated these mechanisms in depth in Epstein-Barr virus-associated nasopharyngeal carcinoma from the endemic area of Southern China. They treated nasopharyngeal carcinoma cell lines with a demethylating agent to re-express silenced genes, profiled the results with messenger RNA microarrays, then used methyl-capture sequencing on biopsy specimens to map methylation across the genome. Two candidates emerged clearly. The gene RRAD, when transfected back into cancer cells, suppressed proliferation, colony formation, and migration. The gene RERG, when overexpressed, produced significantly slower tumor growth and less angiogenesis in mouse xenograft models. A restriction-enzyme-based real-time polymerase chain reaction assay for RERG methylation showed seventy-eight percent sensitivity and one hundred percent specificity as a screening marker in biopsy specimens — numbers that put it in serious biomarker territory. On the microRNA side, miR-497 was consistently downregulated in both nasopharyngeal carcinoma tissue and patient plasma. Restoring miR-497 with mimics suppressed cancer cell growth and migration, induced apoptosis, and slowed tumor growth in xenografts. Inflammation can silence the genes that would stop a tumor from forming, and it can do so invisibly, without leaving a trace in the sequence of those genes. This brings the whole argument to its practical destination: detection. If inflammation leaves molecular fingerprints — oxidative DNA lesions, epigenetic silencing marks, oxidized proteins, circulating microRNAs — those fingerprints could become early-warning signals. Murata frames liquid biopsy as the approach that could make this work clinically: detecting tumor-derived signals in body fluids like blood or urine rather than requiring tissue samples. Blood carries circulating cell-free DNA, extracellular vesicles, and circulating microRNAs, all of which can report on the epigenetic and mutational state of cells far from the needle. The urinary 8-oxodG data from patients infected with Opisthorchis viverrini is the proof of concept: a blood or urine test tracking that lesion level could, in principle, flag the point at which chronic infection is pushing tissue toward malignancy, before cancer is established. The broader picture Murata assembles is one of interconnected damage cascades. Infection triggers inflammation. Inflammation generates reactive oxygen species and reactive nitrogen species. Those reactive species damage DNA, producing mutagenic lesions concentrated in stem-like cells. They damage proteins, liberating iron that amplifies further oxidative stress and disabling the defenses meant to stop it. And they drive epigenetic silencing of tumor suppressor genes, adding a heritable layer of dysfunction on top of the mutational one. Each of these pathways feeds the others. Together, they convert a temporary healing response into a self-sustaining engine of malignancy — and they do it across tissue types, across pathogens, across geographies. The same logic applies in Barrett's esophagus, in oral leukoplakia, in asbestos-exposed lung tissue. Murata closes by noting that this same vicious cycle of oxidative stress and biomacromolecular damage also appears in neurodegenerative disease, suggesting inflammation as a shared thread across multiple chronic pathologies. One in four cancers. That number is not a curiosity. It is a target. This lecture was created by ennepō. Go to https://ennepo.ai to Discover, Create and Follow the latest research in your field. Read when you can. Listen when you want to.