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Study: EGFR Growth Factor Receptor Also Protects Tumor Cells

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Newswise — A growth factor receptor found abundantly on the surface of cancer cells and long known to fuel cancer growth also protects tumor cells from starvation by a newly identified mechanism, researchers at The University of Texas M. D. Anderson Cancer Center report in the May 5 issue of Cancer Cell.

The epidermal growth factor receptor (EGFR) stabilizes another cell membrane protein that channels a constant supply of glucose to cancer cells, saving them from devouring themselves, a team led by Isaiah J. Fidler, D.V.M., Ph.D., professor and chair of M. D. Anderson's Department of Cancer Biology, and Mien-Chie Hung, Ph.D., professor and chair of the department of Molecular and Cellular Oncology.

Their findings could explain why some drugs that target what was previously thought to be EGFR's only role in cancer proliferation have had limited success in patients. Drugs that block EGFR's activation by growth factors - its tyrosine kinase activity -- have gotten response rates in 10 percent to 20 percent of patients across a variety of cancers.

"We show that the receptor is active independent of its kinase activity," Fidler said. "Up until now everyone - including us - focused on kinase, kinase, kinase."

The team shows that EGFR binds to another cell membrane protein called the sodium/glucose co-transporter (SGLT1), protecting SGLT1 from destruction by the cell's proteasome complex, Hung noted. "This complex stabilizes SGLT1 so it continues to transport glucose from the cell membrane into the cell," Hung said.

A "terrific target"

Cancer cells have a high metabolic rate and require more glucose to fuel their activities than do normal cells, Fidler said.

"Inhibiting the kinase activity of the receptor does not interfere with EGFR stabilizing SGLT1, allowing cancer cells to maintain intracellular glucose levels," Fidler said. "To destroy tumor cells by depriving them of glucose one needs to interfere with the receptor per se rather than activation of the receptor. Whether we can target EGFR and therefore interfere with SGLT and therefore interfere with intracellular glucose remains to be seen, but it's a terrific target to shoot for."

The team concludes that it may be necessary to knock down both EGFR's glucose-related role and its growth-inducing kinase activity in order to attack cancers of the epithelium - tissue that lines the surfaces and cavities of the body's organs. Epithelial cancers, or carcinomas, make up 80 percent of all cancers.

EGFR resides on the surface of cell membranes, where epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α) can bind to the receptor, launching a molecular phosphorylation cascade, which stimulates the cell to divide. This normal tyrosine kinase activity is put on overdrive in cancer cells because EGFR is heavily overexpressed on the cell's surface.

Block EGFR and cancer cells die of self-cannibalization

In the current research, the team looked at expression of EGFR but not its kinase activity. They found that blocking expression of the receptor with small interfering RNA killed prostate cancer cells. The cells did not die from apoptosis - programmed cell death that forces a defective cell to commit suicide by destroying its DNA complex and its energy-producing mitochondria.

Rather, these cells died of autophagy - a self-cannibalization response in which a cell under stress or lacking nutrients devours part of its cytoplasm and other organelles to survive. When this response goes on long enough, the cell essentially eats itself until it dies. In cancer research, autophagy is thought to be a second type of programmed cell death.

This self-eating response was also seen in breast cancer and colon cancer cells.

Next, the team measured glucose levels in two sets of prostate cancer cells - one treated by a tyrosine kinase inhibitor and the other with EGFR knocked down by siRNA. Glucose levels were unaffected by the tyrosine kinase inhibitor but fell by 50 percent in the cells with EGFR blocked. The results held in breast and colon cancer cells.

Increasing the level of glucose in the medium that held the cells halted autophagic cell death. These results pointed the team toward glucose transporting proteins. They found that when EGFR was knocked down in a cell, levels of SGLT1 also fell as did glucose levels, resulting in autophagic cell death.

Grants from the National Cancer Institute supported this research, including M. D. Anderson's Specialized Program of Research Excellence (SPORE) in Prostate Cancer and its SPORE in Breast Cancer. First author Zhang Weihua, Ph.D., was partially supported by an Odyssey Fellowship Award from The University of Texas M.D. Anderson Cancer Center.

Co-authors with Fidler, Hung and Weihua are Rachel Tsan and Qiuyu Wu, both of Department of Cancer Biology; and Wei-Chien Huang and Chao-Hwa Chiu, both of the department of Molecular and Cellular Oncology.

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(NewsWise, Medical News, Source: University of Texas M.D. Anderson Cancer Center, May 5, 2008)


The information contained in these articles may or may not be in agreement with my own opinions. They are not posted as medical advice of any kind.

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Neither am I, Carole. :roll:

Wish I were better at it.

However, whenever words as "eating themselves up," "cannibalization," and "apoptosis" are there, they are recognizable as being VERY good events where cancer cells are concerned.

Any work toward that end is encouraging.

It is another step toward what will be many in finding better treatments for cancer survivors.

Anyway - let's hope so.


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This is why EGF-targeted (or VEGF-targeted) drugs are poorly-predicted by measuring the preferred target EGFR (or VEGF). They can be well-predicted by measuring the effect of the drugs on the function of live cells.

There are many pathways to the altered cellular (forest) function, hence all the different “trees” which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.

Many of these drugs cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond.

You still need to measure the net effect of all processes, not just the individual molecular targets.

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Sorry about that Carole. As you may know, for the last two decades, the hallmark of medical treatment for cancer has been intravenous cytotoxic chemotherapy. The drugs targeted rapidly dividing cells, including cancer cells and, of course, certain normal cells (cancer cells and healthy cells). Traditional chemotherapy does not have any mechanism to distinguish between them.

In the last few years, 'targeted' therapies are becoming a component of treatment. 'Targeted' therapy is designed to block a specific gene or protein that has a critical role in the survival, growth, invasion, or metatasis of a specific cancer cell. It takes advantage of the biologic differences between cancer cells and healthy cells by 'targeting' faulty genes or proteins that contribute to the growth and development of cancer.

In other words, 'targeted' treatments fight cancer by correcting or modifying defective 'pathways' in a cancer cell. In healthy cells, each 'pathway' is tightly controlled. For instance, healthy cells are allowed to divide into new cells, and damaged cells are destroyed. However, in cancerous cells, certain points in the 'pathway' become disrupted, usually through a genetic mutation (change in form).

Designing "targeted" anticancer drugs begins with identifying the genes or proteins that are specific to the development of cancer and testing whether blocking those genes or proteins gets rid of the cancer. Genetic (molecular) tests are instrumental in accomplishing this task.

However, understanding 'targeted' treatments begins with understanding the cancer cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific 'pathways' that involve various genes and proteins in a cell.

Genetic testing examines a single process within the cell or a relatively small number of process. The aim is to tell if there is a theoretical predispostion to drug response. Cell-based testing not only examines for the presence of genes and proteins but also for their 'functionality' (their interaction with other genes, proteins, and processes occurring within the cell, and for their response to 'targeted' drugs).

Genetic testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Genetic tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Genetic tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Genetic tests tell us anything about drug combinations.

Cell-based testing looks at 'fresh' living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy. Sometimes a drug will inhibit the 'target' but not stop the growth of cancer. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

As I said above, the are many pathways to altered cellular (forest) function, hence all the different 'trees' which correlate in different situations. Improvement can be made by measuring what happens at the end of all processes (the effects on the forest), rather than the status of the individual trees (pathways/mechanisms). You still need to measure the net effect of all processes, not just the individual molecular (gene/protein) 'targets.'

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Thanks so much. I actually understood your explanation and this is absolutely the closest I've come to having a clue as to what "targeted therapy" means.

I saved your explanation to a file on my hard drive for future reference and cannot thank you enough for posting it!


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