Making cancer cells susceptible to therapeutic attack

A researcher at the University of Illinois at Chicago College of Medicine is discovering how a gene known as E1A, found in a virus responsible for the common cold, renders tumor cells vulnerable to destruction.

“By explaining how E1A works, we hope to develop novel strategies to make human immunological defenses against tumors, as well as chemotherapy and radiation therapy, more effective in combating cancer,” said Dr. James Cook, chief of infectious diseases and a member of the UIC Cancer Center.

The latest study is published in the July 23 issue of the Proceedings of the National Academy of Sciences.

To date, Cook and his colleagues have tested the E1A gene in cancer cells from four species: hamsters, mice, rats and humans. In all four cases, E1A renders the malignancies susceptible to defender cells of the immune system.

“We believe that these observations may reveal a common Achilles heel of many types of cancer cells,” Cook said.

According to Cook, the goal is to find ways to make standard treatments for cancer more effective. Although the disease may respond to the first course of chemotherapy or radiation, typically tumor cells become more resistant later on, when the cancer recurs or metastasizes. The reasons are not clear.

Possibly, series of mutations are acquired as the tumor grows, yielding a naturally selected population of cells capable of thwarting killing agents. The standard clinical course is to change the drug or radiation strategy, but that may not be feasible or useful.

As an alternative, based on the studies Cook is undertaking, physicians may one day be able to alter the resistant malignant tissue itself, making it vulnerable to therapy.

“E1A is helping us identify the set of cellular switches that need to be turned on or off to render cancer cells more sensitive to therapeutic injury,” Cook said.

In the present study, Cook and his colleagues examined a chain of molecular events that occur when cancer cells are confronted with one of the battery of chemicals produced by the immune system. The laboratory experiment mimicked what happens when a tumor begins to grow and the immune system tries to destroy the malignancy.

The chemical used in the study, called tumor necrosis factor, is manufactured primarily by macrophages, which are among the first cells on the scene in an immune response to tumors. When tumor necrosis factor attaches to receptors on the surface of a malignant cell, preparing the way for a full-scale attack, the cancer cell typically blocks the assault.

But when the E1A gene is inserted in the malignant cells, it shuts down the tumor’s defense mechanism. Cook showed that one key step in foiling the defense occurs when E1A gene products bind to cellular retinoblastoma proteins — proteins that normally regulate a cell’s life cycle.

The finding suggests that the E1A gene renders malignant cells susceptible to attack not by interfering with their physiological functioning, but by preventing their use of normal cellular machinery to avoid destruction by the body’s immune defenses.

“Multiple molecular mechanisms triggered by E1A prevent tumor cells from thwarting an immunological attack,” Cook said. “Further definition of these mechanisms will help us develop new concepts that may be useful for treating cancer, in part by enlisting the body to become a more active partner in fighting the disease.”

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