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LACTATE IS CANCER CANDY

Simple Sugar, Lactate, Is Like 'Candy for Cancer Cells': Cancer Cells Accelerate Aging and Inflammation in the Body to Drive Tumor Growth

ScienceDaily (May 26, 2011) — Researchers at the Kimmel Cancer Center at Jefferson have shed new light on the longstanding conundrum about what makes a tumor grow -- and how to make it stop. Interestingly, cancer cells accelerate the aging of nearby connective tissue cells to cause inflammation, which ultimately provides "fuel" for the tumor to grow and even metastasize.

This revealing symbiotic process, which is similar to how muscle and brain cells communicate with the body, could prove useful for developing new drugs to prevent and treat cancers. In this simple model, our bodies provide nourishment for the cancer cells, via chronic inflammation.

"People think that inflammation drives cancer, but they never understood the mechanism," said Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center. "What we found is that cancer cells are accelerating aging and inflammation, which is making high-energy nutrients to feed cancer cells."

In normal aging, DNA is damaged and the body begins to deteriorate because of oxidative stress. "We are all slowly rusting, like the Tin-man in the Wizard of Oz," Dr. Lisanti said. "And there is a very similar process going on in the tumor's local environment." Interestingly, cancer cells induce "oxidative stress," the rusting process, in normal connective tissue, in order to extract vital nutrients.

Dr. Lisanti and his team previously discovered that cancer cells induce this type of stress response (autophagy) in nearby cells, to feed themselves and grow. However, the mechanism by which the cancer cells induce this stress and, more importantly, the relationship between the connective tissue and how this "energy" is transferred was unclear.

"Nobody fully understands the link between aging and cancer," said Dr. Lisanti, who used pre-clinical models, as well as tumors from breast cancer patients, to study these mechanisms. "What we see now is that as you age, your whole body becomes more sensitive to this parasitic cancer mechanism, and the cancer cells selectively accelerate the aging process via inflammation in the connective tissue."

This helps explain why cancers exist in people of all ages, but susceptibility increases as you age. If aggressive enough, cancer cells can induce accelerated aging in the tumor, regardless of age, to speed up the process.

The researchers' findings are being published online June 1st in the journal Cell Cycle in three separate papers.

One paper analyzes the gene profiles of the laser-captured connective tissue, associated with lethal tumors, in human breast cancer patients. In this paper, lethal cancers show the same gene expression pattern associated with normal aging, as well as Alzheimer's disease. In fact, these aging and Alzheimer's disease signatures can identify which breast cancer patients will undergo metastasis. The researchers find that oxidative stress is a common "driver" for both dementia and cancer cell spreading.

In another study, the researchers explain that cancer cells initiate a "lactate shuttle" to move lactate -- the "food" -- from the connective tissue to the cancer cells. There's a transporter that is "spilling" lactate from the connective tissue and a transporter that then "gobbles" it up in the cancer cells."

The implication is that the fibroblasts in the connective tissue are feeding cancer cells directly via pumps, called MCT1 and MCT4, or mono-carboxylate transporters. The researchers see that lactate is like "candy" for cancer cells. And cancer cells are addicted to this supply of "candy."

"We've essentially shown for the first time that there is lactate shuttle in human tumors," said Dr. Lisanti. "It was first discovered nearly 100 years ago in muscles, 15 years ago in the brain, and now we've shown this shuttle also exists in human tumors."

It's all the same mechanism, where one cell type literally "feeds" the other. The cancer cells are the "Queen Bees," and the connective tissue cells are the "Worker Bees." In this analogy, the "Queen Bees" use aging and inflammation as the signal to tell the "Worker Bees" to make more food.

Researchers also identified MCT4 as a biomarker for oxidative stress in cancer-associated fibroblasts, and inhibiting it could be a powerful new anti-cancer therapy.

"If lethal cancer is a disease of "accelerated aging" in the tumor's connective tissue, then cancer patients may benefit from therapy with strong antioxidants and anti-inflammatory drugs," said Dr. Lisanti. "Antioxidant therapy will "cut off the fuel supply" for cancer cells." Antioxidants also have a natural anti-inflammatory action.

 

ONE CHEER FOR NEW COLON CANCER TREATMENT

New treatment regimen shows clinical benefit in advanced colon cancer

May 18th, 2011 in Cancer 

 

A new treatment regimen for patients with metastatic colon cancer appears to offer clinical benefit even when used after multiple other treatments have failed, say research physicians at Georgetown Lombardi Comprehensive Cancer Center, a part of Georgetown University Medical Center.

The research team found that combining a PARP inhibitor with chemotherapy (temozolomide) offers significant benefit in patients who had no further treatment options. However, the study is small, and does not include a comparison arm, so further investigation is needed, they add. The study will be presented in an oral session on Saturday, June 4th, at the 2011 annual meeting of the American Society of Clinical Oncology in Chicago.

PARP, short for "poly (ADP-ribose) polymerase" is a key part of a cell's DNA repair apparatus, and is important for protecting our normal cells against DNA damage. However, cancer cells become resistant to chemotherapy in part by increasing PARP expression and thus rapidly repairing DNA damage intentionally caused by chemotherapy. PARP inhibitors are designed to overcome a cancer cell's ability to repair the damaged DNA. (They are showing promise in both breast and ovarian cancers, and are being studied in a variety of other cancer types).

In this clinical study, doctors administered a potent DNA-damaging chemotherapy, temozolomide, with a PARP inhibitor called ABT-888. The theory is that ABT-888 will diminish the ability of these cancer cells to fix the damage that was just inflicted by the temozolomide, pushing the cancer into a death spiral.

"This is a classic one-two punch: the chemotherapy damages the cancer cells and the PARP inhibitor prevents it from fixing itself, leaving the cell to die," says lead author, Michael Pishvaian, M.D., Ph.D., an assistant professor at Georgetown Lombardi.

This single-arm, phase II study enrolled 49 patients with metastatic disease who were not eligible for surgery and had exhausted all of the standard therapies currently used. Despite having advanced cancer, all study participants were still active at work or home. Researchers found the drug combination controlled cancer growth for nearly six months in 23 percent of the patients, with two patients having a significant reduction in their tumor burden (partial response).

Pishvaian explains, "The treatment was extremely well tolerated, so to have a period of six months with no tumor growth, but also no significant side effects was really meaningful for the patients."

In addition, researchers were able to collect samples of the patients' tumors for further molecular analysis. "By testing tissue samples and identifying their molecular fingerprints, perhaps we can identify which patient subgroups are most likely to respond to this new therapeutic combination," concludes Pishvaian.

Provided by Georgetown University Medical Center

 

"New treatment regimen shows clinical benefit in advanced colon cancer." May 18th, 2011. http://medicalxpress.com/news/2011-05-treatment-regimen-clinical-benefit-advanced.html

 

HEAT TRIGGERS IMMUNE RESPONSE

Scientists show how shifts in temperature prime immune response

May 6th, 2011 in Chemistry / Biochemistry

 

Researchers at The Scripps Research Institute have found a temperature-sensing protein within immune cells that, when tripped, allows calcium to pour in and activate an immune response. This process can occur as temperature rises, such as during a fever, or when it falls—such as when immune cells are "called" from the body's warm interior to a site of injury on cooler skin.

The study, recently published online ahead of print by Nature Chemical Biology, is the first to find such a sensor in immune cells—specifically, in the T lymphocytes that play a central role in activation of killer immune cells. The protein, STIM1, previously known as an endoplasmic reticulum (ER) calcium sensor, had been thought to be important in immune function, and now the scientists show it is also a temperature sensor.

"Temperature has a profound effect on all biological processes including immune responses, but surprisingly little is known about molecules in immune cells that sense temperature sifts," said the study's principal investigator, Scripps Research Professor Ardem Patapoutian. "Here we show that STIM1 senses temperature and has a profound impact on immune cells."

This is the second family of thermosensation molecules that the Patapoutian laboratory has uncovered. The team has isolated and characterized three of six members of the transient receptor potential (TRP) family of ion channels—the so-called thermoTRPs. "These proteins translate temperature, which is a physical stimulus, into a chemical signal—ions flowing into cells," said Patapoutian.

"ThermoTRPs mainly function in specialized sensory neurons that relay environmental temperature information to the brain."

In this study, the researchers turned to immune cells to look for temperature sensors. "Immune cells can experience dramatic temperature changes under either normal or pathophysiological conditions," said first author Bailong Xiao, a research associate in the Patapoutian laboratory. "The temperature drops significantly when, say, immune cells move from the 37 degree Celsius temperature of the spleen to skin, where it is normally 33 degrees. During fever, core body temperature can rise to 41 degrees." Scientists have discussed for decades whether fever is beneficial to the immune system. The researchers believe that identification of a molecular sensor of temperature within immune cells provides a novel avenue to address such questions mechanistically.

The research team, which included Bertrand Coste and Jayanti Mathur, also of the Patapoutian lab, found that STIM1 can be activated by heat with a high degree of temperature sensitivity. Both STIM1 and a plasma membrane pore-forming protein known as Orai1 have recently been identified as essential components of the so-called the calcium release activated calcium (CRAC) channel. But STIM1 had not been known to be heat sensitive until this research, according to Xiao.

The process goes like this: STIM1 proteins are located on the ER, which is the organelle that stores calcium inside the cell. When a sudden change in temperature occurs, STIM1 proteins cluster together and translocate close to the plasma membrane. There, these clusters then can activate Orai1, which leads to the opening of the channel pore and an influx of calcium to activate the cell. Calcium is essential for a number of cellular functions, and, in immune cells, a sustained influx of calcium into these cells activates gene expression and cell proliferation. It turns the immune cell "on," Xiao said.

The function of STIM1 and Orai1 had already been known to be critical to immune function, Xiao said. Mutations in genes encoding either of the proteins lead to development of severe combined immunodeficiency (SCID), the so-called "bubble boy" disease characterized by a complete absence of immunity.

Given the relatively wide expression pattern of STIM1, the researchers suggest that STIM1 may also function as a temperature sensor in other tissues in addition to immune system, including skin, brain, skeletal muscle, and even in blood platelets, all of which could experience moderate but significant temperature changes. For example, temperature-induced STIM1-mediated calcium influx may help muscle cells remodel after exercise, Xiao explained. "We know that calcium is very important for skeletal muscle physiology and remodeling. 
Temperature can rise in skeletal muscles when they are exercised."

The same principle may be working in blood platelets, where STIM1 is also found and plays important roles, he said. When platelets move to the skin surface to repair a cut, the change in temperature may activate STIM1, which can contribute to platelet activation, resulting in formation of a clot, Xiao said.

While sensing temperature is essential for survival and efficient metabolism, it is not clear yet if and how these findings can be clinically translated, said Patapoutian. "It is too early to make predictions on the implications of these findings, but STIM1 and Orai1 are of interest to the pharmaceutical industry given their role in immunodeficiency."

More information: Temperature-dependent STIM1 activation induces Ca2+ influx and modulates gene expression, Nature Chemical Biology (2011) doi:10.1038/nchembio.558

Abstract 
Intracellular Ca2+ is essential for diverse cellular functions. Ca2+ entry into many cell types including immune cells is triggered by depleting endoplasmic reticulum (ER) Ca2+, a process termed store-operated Ca2+ entry (SOCE). STIM1 is an ER Ca2+ sensor. Upon Ca2+ store depletion, STIM1 clusters at ER–plasma membrane junctions where it interacts with and gates Ca2+-permeable Orai1 ion channels. Here we show that STIM1 is also activated by temperature. Heating cells caused clustering of STIM1 at temperatures above 35 °C without depleting Ca2+ stores and led to Orai1-mediated Ca2+ influx as a heat off-response (response after cooling). Notably, the functional coupling of STIM1 and Orai1 is prevented at high temperatures, potentially explaining the heat off-response. Additionally, physiologically relevant temperature shifts modulate STIM1-dependent gene expression in Jurkat T cells. Therefore, temperature is an important regulator of STIM1 function.

Provided by The Scripps Research Institute

 

"Scientists show how shifts in temperature prime immune response." May 6th, 2011. http://www.physorg.com/news/2011-05-scientists-shifts-temperature-prime-immune.html