Microenvironment and inflammation: tumours as wounds that do not heal

The claim. Cancer cells cannot make a tumour alone. They recruit and corrupt normal cells (fibroblasts, macrophages, endothelium, nerves) using the programme of wound healing, and chronic inflammation from infection, irritation or autoimmunity supplies growth factors, survival signals, new vessels and mutagenic oxidants that initiate and promote tumours. In the strong form, the microenvironment is where cancer begins; in the mainstream form, it is an enabling characteristic and a full participant.

Who and when. Virchow described leukocytes in tumours in 1863 and proposed that irritation causes cancer. Dvorak's 1986 essay noted that tumour stroma is generated by the same vascular leak, fibrin deposition and fibroblast activation as granulation tissue. Balkwill and Mantovani (2001) and Coussens and Werb (2002) set out the molecular case for inflammation as a cause; Hanahan and Coussens (2012) catalogued the recruited cells as 'accessories to the crime'; Schäfer and Werner (2008) revisited the overhealing wound. Judah Folkman's angiogenesis hypothesis (1971) and Mina Bissell's microenvironment work are part of the same lineage.

Evidence for. Infections and inflammatory conditions cause cancer: Helicobacter pylori and gastric cancer, hepatitis B and C and liver cancer, ulcerative colitis and colorectal cancer, asbestos and mesothelioma, reflux and oesophageal adenocarcinoma. Long-term aspirin reduces colorectal cancer incidence and cancer death in randomised trial follow-up (Rothwell 2011). Tumour stroma has the cell types and signals of a healing wound, and cancer-associated fibroblasts and tumour-associated macrophages promote growth, invasion and immune exclusion. Anti-inflammatory interleukin-1 beta blockade with canakinumab reduced incident lung cancer in the CANTOS cardiovascular trial. Inflammation became an enabling characteristic in the 2011 hallmarks.

Evidence against and limits. Many cancers arise without recognisable inflammation, and inflammation is also how the immune system attacks tumours: an inflamed, T-cell-rich tumour responds best to checkpoint inhibitors. Anti-inflammatory treatment of established cancer has largely failed: canakinumab did not improve survival in the CANOPY lung cancer trials, and matrix metalloproteinase inhibitors failed in the 1990s. The claim that the microenvironment initiates cancer is hard to separate from the mutations that inflammation causes.

Predictions that held or failed. Held: chronic inflammation is a preventable cause of cancer; removing the cause (H. pylori eradication, hepatitis B vaccination, HPV vaccination, treating hepatitis C) prevents cancer; aspirin prevents colorectal cancer; stroma predicts prognosis. Failed: anti-angiogenic therapy as a broad cure (bevacizumab adds months and resistance follows); anti-inflammatory drugs as treatment for established cancer; stroma depletion in pancreatic cancer (hyaluronidase failed in phase 3).

Therapies that came from it. Aspirin and non-steroidal anti-inflammatory chemoprevention, the HPV and hepatitis B vaccines and H. pylori eradication, anti-VEGF antibodies and kinase inhibitors, and the current trials of fibroblast, macrophage and interleukin targeting. The theory feeds the seed and soil hypothesis (the soil is a microenvironment), the immune surveillance theory and the hallmarks, and it carries forward the tissue organisation field theory's evidence in a form the mainstream accepts.

Status: established for inflammation's role in causing and promoting cancer and for the stroma as a participant; contested as the primary origin of cancer in place of mutation.