Gastroesophageal transformation into cancer

Gastric cancer, oesophageal adenocarcinoma and oesophageal squamous-cell carcinoma (gastroesophageal cancers) are major causes of cancer mortality. Outcomes remain poor, in part because these cancers are commonly diagnosed after they have become locally advanced or metastatic, when treatment is already less likely to succeed. Despite their lethality and substantial unmet need, progress to understand their biology, and to prevent, detect, diagnose, and treat has been limited compared with many other types of cancer.

The burden of gastroesophageal cancers varies markedly across the world. Gastric cancers are especially common in East Asia, Eastern Europe and parts of South America. Oesophageal squamous-cell carcinoma reaches exceptionally high incidence across regions of East Africa, Iran and China. By contrast, the incidence of oesophageal adenocarcinoma has risen markedly over recent decades in many high-income Western populations. These striking differences point to important but poorly understood interactions between inherited susceptibility, infections and environmental exposures, tissue biology and host responses.

Gastroesophageal cancers are biologically distinct diseases and do not follow a single trajectory. Some likely arise through sequential tissue changes leading to metaplasia, dysplasia and eventually cancer. Others may not follow a clearly defined precursor pathway. In both cases this is likely due to persistent exposure, tissue injury, inflammation and altered regeneration. In addition, even where risk factors and precursor conditions are recognised, they do not reliably determine outcome. Histologically normal oesophageal squamous epithelium can contain extensive somatic clones carrying mutations in cancer-associated genes without progressing to malignancy. Furthermore, although Helicobacter pylori infection is a major risk factor for gastric cancer, only a minority of infected people develop the disease. Similarly, only a minority of people with Barrett’s oesophagus progress to oesophageal adenocarcinoma.

Conversely, many people who develop gastroesophageal cancer were not previously recognised as being at high risk. This is particularly important in oesophageal adenocarcinoma, where a high number of cancers are diagnosed outside established Barrett’s oesophagus surveillance programmes.

These observations suggest that exposure, mutational burden, clonal expansion and histological abnormality alone cannot explain who progresses to cancer. Progression may depend on interactions between the cell of origin and its state, tissue architecture, inflammatory and regenerative memory, clonal competition, immune surveillance, stromal and microbial ecosystems, ageing, inherited susceptibility and environmental exposures.

Recognising the urgent need for progress, Cancer Research UK and the Torrey Coast Foundation have partnered to launch a targeted Cancer Grand Challenges funding call on gastroesophageal cancers and seek to fund international teams capable of bringing novel approaches, technologies and thinking to tackle two major challenges.

Oesophageal and gastric adenocarcinomas can develop over years through persistent exposure, tissue injury, inflammation, altered regeneration, metaplasia and clonal selection and outgrowth. This prolonged development may create a window in which early disease can be detected and cancer prevented before it becomes invasive and increasingly autonomous.

Metaplastic tissue can regress, but repeated cycles of injury, regression and re-emergence may act as a biological ratchet, progressively stabilising abnormal cell states and increasing the likelihood of dysplasia. Genetic or epigenetic alterations may subsequently reinforce these states and reduce their dependence on the signals that initiated them. Understanding and manipulating this continuum could enable early tissue changes to be restored to normal, while more advanced abnormal states might be eliminated, durably controlled or redirected into terminal, non-malignant fates.

The cells from which these cancers arise, the epithelial states they adopt and the immune, inflammatory, stromal and microbial processes that initiate, sustain or constrain their progression remain incompletely understood. Different oesophageal adenocarcinomas may also follow distinct trajectories. Furthermore, many oesophageal adenocarcinomas are diagnosed in people who were not previously diagnosed with Barrett’s oesophagus.

This challenge seeks to define the biological mechanisms that initiate, sustain and drive the progression of early oesophageal and gastric adenocarcinomas, and to use this understanding to determine whether early tissue changes can be reversed, durably halted or redirected away from malignant progression.

Note that this challenge excludes investigating the transition to, and from, Barrett’s oesophagus, recognising the large number of spontaneous oesophageal adenocarcinomas that appear to arise in the absence of Barrett’s.

Potential questions that could be addressed by teams include, but are not limited to, identifying the cell of origin of oesophageal and gastric adenocarcinomas, the biological mechanisms that drive their initiation, and the influence of ageing, environmental exposures, and immune responses on these processes.

Applications should focus on early tissue change en route to tumour initiation to develop a deeper understanding of disease risk for future prevention programs. Studies of established cancer or experimental models of established cancer may be included where they directly illuminate the initiation of early human disease. Teams are encouraged to develop enabling technologies where existing approaches cannot identify, reconstruct or manipulate the relevant biological transitions.

If clear biological mechanisms are identified which govern initiation and progression, teams may seek to reverse them. Potential approaches might include but not be limited to restoring normal differentiation, reversing inflammatory or epigenetic memory, disrupting essential tissue dependencies, activating protective immunity or redirecting abnormal cells away from malignant progression.

Why do we urgently need new ways to prevent cancers of the stomach and oesophagus? 

Cancers of the stomach and oesophagus (the food pipe) are major causes of cancer death worldwide. Worldwide, nearly 1.5 million new cases of stomach and oesophageal cancer were estimated in 2024. Together, these cancers caused more than 1 million deaths, over one in ten cancer deaths worldwide. They are often found only after they have spread, when treatment is less likely to work.  Researchers still cannot reliably predict who will develop these cancers. Nor can they fully explain why these cancers affect some populations far more than others.

Some risk factors and warning signs are known. For example, infection with the bacteria Helicobacter pylori can lead to tissue damage, which can increase stomach cancer risk. Barrett's oesophagus, a condition where the lining of the lower food pipe changes, can sometimes lead to oesophageal cancer. But most people with these risk factors never develop cancer, while many people who do develop cancer were not previously thought to be at high risk. Known risk factors therefore do not tell the whole story.

Cancer Research UK and the Torrey Coast Foundation are asking international teams to tackle two connected questions: what drives the earliest tissue changes towards cancer? And what causes the striking differences in cancer rates around the world? Answering these questions could make it possible to identify risk more accurately and prevent these cancers.