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Cancer Cells “Reprogram” Energy Needs to Grow and Spread

Studying a rare inherited syndrome, researchers at Johns Hopkins have found that cancer cells can reprogram themselves to turn down their own energy-making machinery and use less oxygen, and that these changes might help cancer cells survive and spread.

The Hopkins scientists report that the loss of a single gene in kidney cancer cells causes them to stop making mitochondria, the tiny powerhouses of the cell that consume oxygen to generate energy.

Instead, the cancer cells use the less efficient process of fermentation, which generates less energy but does not require oxygen. As a result, the cancer cells must take in large amounts of glucose. The appetite of cancer cells for glucose is so great that it can be used to identify small groups of tumor cells that have spread throughout the body.

Although changes in mitochondria have been described in many cancers, the Hopkins study shows for the first time how a cancer-causing mutation can block their production.

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“There must be a strong advantage to cancer cells to stop using a highly efficient process in favor of one that generates much less energy,” says Gregg Semenza, M.D., Ph.D., professor of pediatrics and director of the vascular biology program in the Institute for Cell Engineering at Johns Hopkins.

But turning down the “thermostat” in a sense, may give the cancer cell a survival edge. Reporting in the May 8 issue of Cancer Cell, Semenza and his colleagues found that if they reversed the switch and forced kidney cancer cells to start making mitochondria again, the cells produced increased amounts of free radicals, which can cause cells to stop dividing or even die.

Semenza’s team uncovered the mitochondrial mechanism in a study of Von Hippel-Lindau (VHL) syndrome, caused by a single gene mutation and characterized by the tendency to develop tumors in many parts of the body, including the kidney, brain and adrenal glands.

Semenza and colleagues measured mitochondria content and oxygen use in kidney cancer cells that contain no VHL protein and in the same cells with VHL “engineered” back in. Restoring VHL caused the cells to make two to three times more mitochondria and use two to three times more oxygen.

VHL normally blocks the action of HIF-1, a protein that the Hopkins group discovered in 1992. Cells normally make HIF-1 only under low oxygen conditions, when fermentation is necessary to make energy. However, in the absence of VHL, HIF-1 is active even when oxygen is plentiful and switches on genes that help a cell take up more glucose.

This current work shows that excess HIF-1 counteracts a protein called MYC, which normally stimulates cells to make mitochondria. “Because MYC is turned on in many other cancers, these results suggest that shutting down the mitochondria must be a very important event in kidney cancer,” Semenza notes.

There is currently no treatment available for patients with advanced kidney cancer. Scientists at pharmaceutical companies, the National Cancer Institute, and laboratories at Hopkins and other universities are investigating whether drugs that inhibit HIF-1 may be useful for cancer therapy.

The research was funded by the National Institutes of Health.

Authors on the paper are Huafeng Zhang, Ping Gao, Ryo Fukuda, Balaji Krishnamachary, Karen Zeller, Chi V. Dang and Semenza of Hopkins, and Ganesh Kumar of the University of Chicago.

On the Web:
http://www.hopkins-ice.org/index.html
http:/http://www.cancercell.org/

Key Points
Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth (see Questions 1, 2, and 3).
Because scientists call these molecules “molecular targets,” therapies that interfere with them are sometimes called “molecular-targeted drugs,” “molecularly targeted therapies,” or other similar names (see Question 1).
The National Cancer Institute’s Molecular Targets Development Program is working to identify and evaluate molecular targets (see Question 6).

What are targeted cancer therapies?

Targeted cancer therapies use drugs that block the growth and spread of cancer. They interfere with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. Because scientists call these molecules “molecular targets,” these therapies are sometimes called “molecular-targeted drugs,” “molecularly targeted therapies,” or other similar names. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.

Most targeted cancer therapies are in preclinical testing (research with animals), but some are in clinical trials (research studies) or have been approved by the U.S. Food and Drug Administration (FDA). Targeted cancer therapies are being studied for use alone, in combination with each other, and in combination with other cancer treatments, such as chemotherapy.

What are some of the cellular changes that lead to cancer?

Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place. Sometimes this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. These extra cells can form a mass of tissue called a growth or tumor. The cells in malignant (cancerous) tumors are abnormal and divide without control or order. They can invade and damage nearby tissues and organs. Also, cancer cells can break away from a malignant tumor and spread to other parts of the body.

Normal cell growth and division are largely under the control of a network of chemical and molecular signals that give instructions to cells. Genetic alterations (changes) can disrupt the signaling process so that cells no longer grow and divide normally, or no longer die when they should. Alterations in two types of genes can contribute to the cancer process. Proto-oncogenes are normal genes that are involved in cell growth and division. Changes in these genes lead to the development of oncogenes, which can promote or allow excessive and continuous cell growth and division. Tumor suppressor genes are normal genes that slow down cell growth and division. When a tumor suppressor gene does not work properly, cells may be unable to stop growing and dividing, which leads to tumor growth.

To use the metaphor of a car, the presence of an oncogene is like having a gas pedal that is stuck to the floorboard, causing cells to continually grow and divide. Tumor suppressor genes act like a brake pedal. The loss of a functioning tumor suppressor gene is like having a brake pedal that does not work properly, allowing cells to continually grow and divide.

Genetic changes that are not corrected by the cell can lead to the production of abnormal proteins. Normally, proteins interact with each other as a kind of relay team to carry out the work of the cell. For example, when molecules called growth factors (GFs) attach to their corresponding growth factor receptors (GFRs) on the surface of the cell, a process carried out by proteins signals the cell to divide. Damaged proteins may not respond to normal signals, may over-respond to normal signals, or otherwise fail to carry out their normal functions. Cancer develops when abnormal proteins inside a cell cause it to reproduce excessively and allow that cell to live longer than normal cells.

How do targeted cancer therapies work?

Targeted cancer therapies interfere with cancer cell growth and division in different ways and at various points during the development, growth, and spread of cancer. Many of these therapies focus on proteins that are involved in the signaling process. By blocking the signals that tell cancer cells to grow and divide uncontrollably, targeted cancer therapies can help to stop the growth and division of cancer cells.

What are some types of targeted cancer therapies?

Targeted cancer therapies include several types of drugs. Some examples are listed below:

“Small-molecule” drugs block specific enzymes and GFRs involved in cancer cell growth. These drugs are also called signal-transduction inhibitors. Gleevec® (STI–571 or imatinib mesylate) is a small-molecule drug approved by the FDA to treat gastrointestinal stromal tumor (a rare cancer of the gastrointestinal tract) and certain kinds of chronic myeloid leukemia (1, 2). Gleevec targets abnormal proteins, or enzymes, that form inside cancer cells and stimulate uncontrolled growth. Iressa® (ZD1839 or gefitinib) is approved by the FDA to treat advanced non-small cell lung cancer. This drug targets the epidermal growth factor receptor (EGFR), which is overproduced by many types of cancer cells. Other small-molecule drugs are being studied in clinical trials in the United States.

“Apoptosis-inducing” drugs cause cancer cells to undergo apoptosis (cell death) by interfering with proteins involved in the process. Velcade® (bortezomib) is approved by the FDA to treat multiple myeloma that has not responded to other treatments (3). Velcade causes cancer cells to die by blocking enzymes called proteasomes, which help to regulate cell function and growth. Another apoptosis-inducing drug called Genasense™ (oblimersen), which is only available in clinical trials, is being studied to treat leukemia, non-Hodgkin’s lymphoma, and solid tumors. Genasense blocks the production of a protein known as BCL–2, which promotes the survival of tumor cells. By blocking BCL–2, Genasense leaves the cancer cells more vulnerable to anticancer drugs.

Monoclonal antibodies, cancer vaccines, angiogenesis inhibitors, and gene therapy are considered by some to be targeted therapies because they interfere with the growth of cancer cells. Information about these treatments can be found in the following National Cancer Institute (NCI) fact sheets, which are available on the Internet or by calling the Cancer Information Service (CIS) (see below):
—Biological Therapies for Cancer: Questions and Answers includes information about monoclonal antibodies and cancer vaccines. This fact sheet is available at http://www.cancer.gov/cancertopics/factsheet/Therapy/biological on the Internet.

—Herceptin® (Trastuzumab): Questions and Answers contains information about Herceptin, which is a monoclonal antibody. This fact sheet can be found at http://www.cancer.gov/cancertopics/factsheet/Therapy/herceptin on the Internet.

—Angiogenesis Inhibitors in the Treatment of Cancer is available at http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-inhibitors on the Internet.

—Gene Therapy for Cancer: Questions and Answers can be found at http://www.cancer.gov/cancertopics/factsheet/Therapy/gene on the Internet.

What impact will targeted therapies have on cancer treatment?

Targeted cancer therapies will give doctors a better way to tailor cancer treatment. Eventually, treatments may be individualized based on the unique set of molecular targets produced by the patient’s tumor. Targeted cancer therapies also hold the promise of being more selective, thus harming fewer normal cells, reducing side effects, and improving the quality of life.

What are some resources for more information?

The NCI’s Molecular Targets Development Program (MTDP) is working to identify and evaluate molecular targets that may be candidates for drug development. As part of the NCI’s Center for Cancer Research, the MTDP provides research support for NCI-designated, high-priority drug discovery, development, and research focused on specific molecular targets, pathways, or processes. The MTDP’s Web site is http://home.ncifcrf.gov/mtdp/ on the Internet.

Information about clinical trials is available from the CIS (see below). Information specialists at the CIS use PDQ®, the NCI’s cancer information database, to identify and provide detailed information about specific ongoing clinical trials. PDQ includes all NCI-funded clinical trials and some studies conducted by independent investigators at hospitals and medical centers in the United States and other countries around the world.

People also have the option of searching for clinical trials on their own. The clinical trials page of the NCI’s Web site, located at http://www.cancer.gov/clinicaltrials/ on the Internet, provides information about clinical trials and links to PDQ.

Selected References

Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New England Journal of Medicine 2002; 347(7):472–480.

Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. New England Journal of Medicine 2002; 346(9):645–652.

Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. New England Journal of Medicine 2003; 348(26):2609–2617.

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Related Resources

Publications (available at http://www.cancer.gov/publications)

National Cancer Institute Fact Sheet 2.11, Clinical Trials: Questions and Answers
National Cancer Institute Fact Sheet 7.2, Biological Therapies for Cancer: Questions and Answers
National Cancer Institute Fact Sheet 7.18, Gene Therapy for Cancer: Questions and Answers
National Cancer Institute Fact Sheet 7.42, Angiogenesis Inhibitors in the Treatment of Cancer
National Cancer Institute Fact Sheet 7.45, Herceptin® (Trastuzumab): Questions and Answers
What You Need To Know About™ Cancer

National Cancer Institute (NCI) Resources

Cancer Information Service (toll-free)
Telephone: 1–800–4–CANCER (1–800–422–6237)
TTY: 1–800–332–8615

Online
NCI’s Web site: http://www.cancer.gov
LiveHelp, NCI’s live online assistance:
https://cissecure.nci.nih.gov/livehelp/welcome.asp

Key Points
Cancer occurs when cells become abnormal and grow without control (see Question 1).
The place where the cancer started is called the primary cancer or the primary tumor (see Question 2).
Metastatic cancer occurs when cancer cells spread from the place where the cancer started to other parts of the body (see Question 3).
When cancer spreads, the metastatic cancer has the same type of cells and the same name as the primary tumor (see Question 3).
The most common sites of metastasis are the lungs, bones, liver, and brain (see Question 4).
Treatment for metastatic cancer usually depends on the type of cancer as well as the size and location of the metastasis (see Question 8).

What is cancer?

Cancer is a group of many related diseases. All cancers begin in cells, the building blocks that make up tissues. Cancer that arises from organs and solid tissues is called a solid tumor. Cancer that begins in blood cells is called leukemia, multiple myeloma, or lymphoma.

Normally, cells grow and divide to form new cells as the body needs them. When cells grow old and die, new cells take their place. Sometimes this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should.

The extra cells form a mass of tissue, called a growth or tumor. Tumors can be either benign (not cancerous) or malignant (cancerous). Benign tumors do not spread to other parts of the body, and they are rarely a threat to life. Malignant tumors can spread (metastasize) and may be life threatening.

What is primary cancer?

Cancer can begin in any organ or tissue of the body. The original tumor is called the primary cancer or primary tumor. It is usually named for the part of the body or the type of cell in which it begins.

What is metastasis, and how does it happen?

Metastasis means the spread of cancer. Cancer cells can break away from a primary tumor and enter the bloodstream or lymphatic system (the system that produces, stores, and carries the cells that fight infections). That is how cancer cells spread to other parts of the body.

When cancer cells spread and form a new tumor in a different organ, the new tumor is a metastatic tumor. The cells in the metastatic tumor come from the original tumor. This means, for example, that if breast cancer spreads to the lungs, the metastatic tumor in the lung is made up of cancerous breast cells (not lung cells). In this case, the disease in the lungs is metastatic breast cancer (not lung cancer). Under a microscope, metastatic breast cancer cells generally look the same as the cancer cells in the breast.

Where does cancer spread?

Cancer cells can spread to almost any part of the body. Cancer cells frequently spread to lymph nodes (rounded masses of lymphatic tissue) near the primary tumor (regional lymph nodes). This is called lymph node involvement or regional disease. Cancer that spreads to other organs or to lymph nodes far from the primary tumor is called metastatic disease. Doctors sometimes also call this distant disease.

The most common sites of metastasis from solid tumors are the lungs, bones, liver, and brain. Some cancers tend to spread to certain parts of the body. For example, lung cancer often metastasizes to the brain or bones, and colon cancer frequently spreads to the liver. Prostate cancer tends to spread to the bones. Breast cancer commonly spreads to the bones, lungs, liver, or brain. However, each of these cancers can spread to other parts of the body as well.

Because blood cells travel throughout the body, leukemia, multiple myeloma, and lymphoma cells are usually not localized when the cancer is diagnosed. Tumor cells may be found in the blood, several lymph nodes, or other parts of the body such as the liver or bones. This type of spread is not referred to as metastasis.

Are there symptoms of metastatic cancer?

Some people with metastatic cancer do not have symptoms. Their metastases are found by x-rays and other tests performed for other reasons.

When symptoms of metastatic cancer occur, the type and frequency of the symptoms will depend on the size and location of the metastasis. For example, cancer that spreads to the bones is likely to cause pain and can lead to bone fractures. Cancer that spreads to the brain can cause a variety of symptoms, including headaches, seizures, and unsteadiness. Shortness of breath may be a sign of lung involvement. Abdominal swelling or jaundice (yellowing of the skin) can indicate that cancer has spread to the liver.

Sometimes a person’s primary cancer is discovered only after the metastatic tumor causes symptoms. For example, a man whose prostate cancer has spread to the bones in his pelvis may have lower back pain (caused by the cancer in his bones) before he experiences any symptoms from the primary tumor in his prostate.

How does a doctor know whether a cancer is a primary or a metastatic tumor?

To determine whether a tumor is primary or metastatic, a pathologist examines a sample of the tumor under a microscope. In general, cancer cells look like abnormal versions of cells in the tissue where the cancer began. Using specialized diagnostic tests, a pathologist is often able to tell where the cancer cells came from. Markers or antigens found in or on the cancer cells can indicate the primary site of the cancer.

Metastatic cancers may be found before or at the same time as the primary tumor, or months or years later. When a new tumor is found in a patient who has been treated for cancer in the past, it is more often a metastasis than another primary tumor.

Is it possible to have a metastatic tumor without having a primary cancer?

No. A metastatic tumor always starts from cancer cells in another part of the body. In most cases, when a metastatic tumor is found first, the primary tumor can be found. The search for the primary tumor may involve lab tests, x-rays, and other procedures. However, in a small number of cases, a metastatic tumor is diagnosed but the primary tumor cannot be found, in spite of extensive tests. The pathologist knows the tumor is metastatic because the cells are not like those in the organ or tissue in which the tumor is found. Doctors refer to the primary tumor as unknown or occult (hidden), and the patient is said to have cancer of unknown primary origin (CUP). Because diagnostic techniques are constantly improving, the number of cases of CUP is going down. More information about CUP can be found in the National Cancer Institute (NCI) fact sheet Cancer of Unknown Primary Origin, which is available at http://www.cancer.gov/cancertopics/factsheet/Sites-Types/unknownprimary on the Internet.

What treatments are used for metastatic cancer?

When cancer has metastasized, it may be treated with chemotherapy, radiation therapy, biological therapy, hormone therapy, surgery, cryosurgery, or a combination of these. The choice of treatment generally depends on the type of primary cancer, the size and location of the metastasis, the patient’s age and general health, and the types of treatments the patient has had in the past. In patients with CUP, it is possible to treat the disease even though the primary tumor has not been located. The goal of treatment may be to control the cancer, or to relieve symptoms or side effects of treatment.

Are new treatments for metastatic cancer being developed?

Yes, many new cancer treatments are under study. To develop new treatments, the NCI sponsors clinical trials (research studies) with cancer patients in many hospitals, universities, medical schools, and cancer centers around the country. Clinical trials are a critical step in the improvement of treatment. Before any new treatment can be recommended for general use, doctors conduct studies to find out whether the treatment is both safe for patients and effective against the disease. The results of such studies have led to progress not only in the treatment of cancer, but in the detection, diagnosis, and prevention of the disease as well. Patients interested in taking part in a clinical trial should talk with their doctor.

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Related Resources

Publications (available on http://www.cancer.gov/publications)

National Cancer Institute Fact Sheet 5.32, Staging: Questions and Answers
National Cancer Institute Fact Sheet 6.7, Cancer: Questions and Answers
National Cancer Institute Fact Sheet 6.19, Cancer of Unknown Primary Origin
What You Need To Know About™ Cancer

National Cancer Institute (NCI) Resources

Cancer Information Service (toll-free)
Telephone: 1–800–4–CANCER (1–800–422–6237)
TTY: 1–800–332–8615

Online
NCI’s Web site: http://www.cancer.gov
LiveHelp, NCI’s live online assistance:
https://cissecure.nci.nih.gov/livehelp/welcome.asp