Prognostic role of side where colon cancer occurs

It has been suggested that localization of colon cancer on either the right or left side may influence prognosis because of differing biological features. Clinical presentation for right and left colon cancer can differ and right and left colon cancers are also genetically distinct. A review and meta-analysis by Fausto Petrelli, M.D., of the ASST … Continue reading “Prognostic role of side where colon cancer occurs”

It has been suggested that localization of colon cancer on either the right or left side may influence prognosis because of differing biological features. Clinical presentation for right and left colon cancer can differ and right and left colon cancers are also genetically distinct.

A review and meta-analysis by Fausto Petrelli, M.D., of the ASST Bergamo Ovest, Treviglio, Italy, and coauthors included 66 studies and more than 1.4 million patients with a median follow-up of 65 months.

Left-sided primary tumor location was associated with a nearly 20 percent reduced risk of death, according to the analysis. This difference was independent of many clinical factors like tumor stage and receipt of adjuvant chemotherapy. The authors note a number of possible reasons for this apart from biological differences.

The authors note limitations to their study, which cannot establish causality.

“Based on the results of this study, the side of origin of CC [colon cancer] (left vs. right) should be acknowledged as a criterion for establishing prognosis in both earlier and advanced stages of disease. Moreover, primary tumor locations should be carefully considered when deciding treatment intensity in metastatic and locoregional settings, and should represent an important stratification factor for future adjuvant studies,” the article concludes.

Study yields rich dossier of cancer-linked protein’s associates

The discovery is the result of a detailed study of PP2A’s structure down to the atomic level by a team of four scientists at Brown University and one in Leuven, Belgium. By determining exactly how PP2A physically binds with other proteins, the scientists were able to figure out which other proteins are a strong fit. Most of the proteins on the list are news to the biological community.

Moreover, the study data could help scientists to predict how strongly each protein, or “substrate” binds PP2A. It could also offer clues on how to prevent a binding if it turns out to be disease-causing, for instance because it misregulates a process in a cell.

“PP2A is a very important enzyme, but identifying its substrates and its regulators has been exceptionally difficult and part of the reason is we didn’t understand how they were engaging with this protein,” said corresponding author Rebecca Page, a Professor of molecular biology, cellular biology and biochemistry at Brown University and corresponding author of the paper in the journal Structure.

Binding findings

Brown graduate student Xinru Wang and postdoctoral researcher Rakhi Bajaj led the effort to find PP2A’s closest binding partners. Their main strategy was to bind the regulatory subunit of PP2A, called B56, with three shortened versions of two proteins already known to be associated: “BubR1” and “RepoMan.” They made each of those protein complexes into crystals, which can be analyzed in atomic detail using X-rays. This procedure gave them a close look at which key binding interactions were consistent and which other interactions made each union unique.

“The similarities were the common features that we used to identify additional PP2A interactors,” Wang said.

And, Page added, “The differences between RepoMan and BubR1 was what allowed us to explain why the binding affinities were different and how different PP2A regulators might be competing in the cell.”

One of the key similarities they observed, for example, was that PP2A has two distinct pockets at a key location on its surface where other proteins can dock if they have the right protrusions.

A key difference they noticed is that RepoMan’s binding is much stronger than that of BubR1 and they could discern structurally why that was — RepoMan builds an extra “salt bridge” to solidify its connection.

Making a list

The researchers used these observations and others made from studying the three crystallized bindings to guide a search of databases of human proteins. By looking for specific amino acid sequences in proteins the scientists were able to tell how well they might fold up and bind to PP2A.

Page said that with conservative criteria — looking only for the best and most likely matches — they found 98 proteins with strong likelihoods. A few of them were already known to associate with PP2A — confirming that the approach makes sense — but many more are novel.

Biologists can now study and tinker with the newly identified proteins to see whether any of them conspire with PP2A to throw processes such as cell division out of whack, leading to tumor growth, Page said.

“These new proteins provide targets that we can now go investigate in detail in cells to see what consequences changing these sequences have on their activity,” she said.

The team has already seen some potential links in their new data to cancer, Bajaj said. For example, a mutation that replaces amino acid Histidine 243 on PP2A-B56 is found in germ cell tumors (called Embryonal carcinoma). The data might help explain why. The team saw that this amino acid makes particularly important contacts in PP2A binding to its partners.

Research into basic workings of immune system points to way of improving therapies for cancer

An accompanying study led by researchers at the University of Pennsylvania and co-authored by Dana-Farber scientists reports that these differences in circuitry remain largely unchanged by a type of cancer immunotherapy known as checkpoint inhibition, potentially closing off one avenue of improving this technique.

The pair of studies bring renewed focus to the epigenetics of T cells — the multilayered system of molecular switches, accelerators, and throttles that controls the activity of genes. Scientists have known for years that the pattern of genes is different in exhausted T cells than in functional T cells that are fully engaged in fighting disease, but the actual extent of these differences has been uncertain.

One difference that is clear is that exhausted T cells express the programmed cell death protein-1 (PD-1), which commands them not to attack normal, healthy cells, but can also prevent them from striking at cancerous or chronically infected cells. Blocking PD-1 with checkpoint-inhibiting drugs — and thereby restoring the cancer-killing zeal of T cells — has become one of the most successful new approaches to cancer treatment in nearly a decade.

“Exhausted T cells display a variety of functional defects,” says Nicholas Haining, BM, BCH, of Dana-Farber/Boston Children’s, senior author of the new paper. “They are paralyzed and don’t have the fire-power to destroy cancer or virally-infected cells. For us, the question in this study was, do exhausted cells represent a distinct type of T cell or are they merely a ‘groggy’ version of functional T cells?”

With chronically infected mice as their model, the researchers used a new technology called ATAC-seq to map the regulatory regions of the genome — the sections of DNA involved in switching genes on and off — in the animals’ exhausted and functional CD8+ T cells. (CD8+ T cells are programmed to identify and eliminate cancerous and infected cells.)

“We found the landscape of regulatory regions to be fundamentally different in exhausted and functional T cells,” Haining says. “There were thousands of instances where a regulatory region appeared in exhausted T cells but not in their functional counterparts, and vice versa. This tells us that the two types of cells use very different wiring diagrams to control their gene activity.”

The researchers then tested whether removing a regulatory stretch of DNA that spurs the production of PD-1 would drive down expression of the protein. Using CRISPR/Cas9 technology, they snipped out that region and indeed, PD-1 expression dropped.

The success of this experiment may offer the key to improving CAR T cell therapy. CAR T cells are T cells that are removed from a patient, genetically engineered to grow a protein “sensor” that targets them to tumor cells, and then re-injected into the patient. The hope is that these retrofitted T cells will be better able to track down cancer cells, particularly in leukemia.

However, one of the shortcomings of CAR T cells is that they tend to become exhausted. The work described in the new study suggests that while T cells are being engineered to produce the sensor, they could also be re-tooled to delete the genetic wiring that causes them to express excessive levels of PD-1 or other exhaustion genes. The resulting CAR T cells would not only be better at stalking cancer, but also more aggressive about attacking it.

In the companion paper, researchers explored whether blocking the PD-1 checkpoint rewired exhausted T cells to make them, from an epigenetic standpoint, more like functional T cells. Using chronically infected mouse models, as in the first study, the investigators found that while such gain of function does occur briefly, the epigenetic switches from its previous, exhausted state remain largely unchanged.

“This suggests that the benefits achieved by checkpoint blockade result from a transient revving up of exhausted T cells, not a permanent reshaping of their state,” Haining says.

The findings of the two studies point to the need for a comprehensive atlas of the regulatory regions that are active in exhausted and functional T cells, he continues. Such a guide would provide targets for rewiring T cells with genetic engineering or epigenetic drugs to make them more effective cancer killers.