Evolution is key for all living beings to survive and thrive on Earth and cancer cells are no different as they too have to go through their own evolutionary cycle – though destructive to humans – to ensure their existence.
Researchers at ASU’s Biodesign Institute led an international team and looked at how evolution principle are applicable even in case of cells – specifically cancer cells – what how these cells take a rather destructive form. For the study researchers focused on a condition known as Barrett’s Esophagus (BE). In this particular diseases cells lining the throat change shape from their normal form (known as squamous epithelia) to a pathological cell type (known as columnar epithelia).
Studies have shown that of all the BE patients – a very small number, roughly around .2 percent per year – go on to develop highly lethal, treatment-resistant cancer, known as Esophageal Adenocarcinoma (EAC). While there hvae been advances that have developed therapies to deal with EAC, prospects for EAC patients remain bleak–fewer than 15 percent survive beyond 5 years.
The scientific community has been looking at answering the question of why only a very small number of BE patients go on to develop EAC and what causes is evolution.
Authors of the latest study published in Nature Communications believe a better understanding of the evolutionary dynamics of this process may hold the key. The study examines these dynamics over at least 6 years of surveillance. Of the 8 BE patients examined, 4 remain stable and 4 progress to cancer.
Currently methods of predicting which BE patients will end up developing EAC are completely unreliable and impractical owing to the processes involved. Better predictions will rely in part on testing BE samples at multiple points in time, and an examination of cells extracted from different locations in the esophageal tissue. One positive consequence of aggressive BE cell surveillance is that it has provided researchers with a rich library of data that can be mined using new methods in order to tease out critical factors governing progression vs non-progression to cancer.
Barrett’s Esophagus can develop over time when digestive acid backs up from the stomach into the esophagus, causing damage and growth of precancerous cells. To accurately assess the evolutionary dynamics involved in progression to cancer, researchers need more fine-grained analyses of BE cells, to tease out details that may not be detectable in whole biopsies containing millions of cells.
The study focused on losses and gains of large regions of chromosomes in the BE cells. Aberrations in the chromosomes are high in those who go on to develop EAC, even 4 years before progression and remain low in non-progressors, pointing to the value of chromosomal diversity as a diagnostic indicator.
The study also examined a phenomenon known as genome doubling. This results from faulty cell division, which creates a cell with twice the normal number of chromosomes. Those likely to progress to EAC were also more likely to experience genome doubling, which is presaged by an increasing rate of accumulation of chromosomal aberrations.
The study examines genetic variation in BE crypts, comparing these with the variation found through examination of biopsies. Multiple biopsies and crypt samples were examined from 8 BE patients at two different time points. Four of these patients progressed to EAC and 4 did not.
Results comparing biopsy and single crypt information show that genetic alterations are indeed rare, even at the crypt level, and that Barrett’s lesions tend to arise from a single ancestral cell gone awry. Further, the study selects cells from different regions of the esophagus and finds that genetic alterations were more common in samples taken near the base of the esophagus, known as the gastro-esophageal junction.
The study addresses five previously unanswered questions concerning BE. As the authors stress, the results offer new insights into the general process of cell progression to cancer, which may be applicable across many, if not all forms of the disease.
Results indicate that
1. BE tissue in most cases arises from a single altered ancestral cell
2. expansion of cancerous clones (identical cells of common ancestry) is rare
3. cells sampled near the gastro-esophageal junction accumulate more genomic alterations than those found in other regions of the esophagus, making them better targets for diagnosis
4. there are dramatic changes in mutation rate during progression and these may occur early in the process of cancer progression and
5. genetic diversity as measured through biopsy in Barrett’s patients is comparable to that observes in individual crypts, indicating that biopsy analysis is adequate for assessing the evolutionary characteristics of BE cells and their likelihood of progression.
Continued work in this area promises to untangle the complex network of evolutionary factors at play when cells are directed away from their normal course and toward the fateful path of cancer.