Cancer

DNA sequences from tumor cells can be used to direct the immune system to attack cancer, according to scientists at Washington University School of Medicine in St. Louis.

The research, in mice, appears online in Nature.

The immune system relies on an intricate network of alarm bells, targets and safety brakes to determine when and what to attack. The new results suggest that scientists may now be able to combine DNA sequencing data with their knowledge of the triggers and targets that set off immune alarms to more precisely develop vaccines and other immunotherapies for cancer.

"We already have ways to identify specific targets for immunotherapy, but they are technically challenging, extremely labor-intensive and often take more than a year to complete," says senior author Robert Schreiber, PhD, the Alumni Professor of Pathology and Immunology at the School of Medicine and co-leader of the tumor immunology program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "These difficulties have stood in the way of developing personalized immunotherapies for cancer patients, who often require immediate care for their disease. To our knowledge, this is one of the first studies to show that the faster methods provided by DNA sequencing can help. That opens up all kinds of exciting possibilities."

Scientists have long maintained that the immune system can recognize cancer as a threat either on its own or with the help of vaccines or other immunotherapeutic treatments, which help alert the immune system to the danger posed by cancers. Once the cancer is recognized, the immune system should develop the capacity to attack growing cancer cells until either the tumor is eradicated or the immune system's resources are exhausted.

Schreiber and his colleagues have shown that interactions between the immune system and cancer are more complex. Their theory, called cancer immunoediting, suggests that some of the mutations in tumor cells are very easy for the immune system to recognize as a threat. If the immune system detects these mutations in cancer cells, it attacks until they are destroyed.

At that point, the cancer may be eliminated. But it's also possible that the cancer can be "edited" by the immune system, resulting in the removal of all the cells containing the critical easily recognized mutations. The remaining tumor cells can continue to grow or enter into a period of dormancy where they are not destroyed but are held in check by the immune system.

For the new study, Schreiber and his colleagues wanted to define the genetics of tumors that had yet to interact with the immune system. To do so, they induced tumors in mice with disabled immune systems. They collaborated with Washington University's Genome Institute scientists, who sequenced the cancer cells' genes.

"Until very recently, this work would have been impractical because of the costs involved," Schreiber says. "But the technology has improved and prices have come down, and now it's possible to obtain this genetic information for a few thousand dollars instead of a million."

By comparing genetic data from cancer cells and normal cells, scientists identified 3,743 mutations in the genes of the tumor cells. Next, they turned to an online database of protein sequences likely to be recognized by a key immune system sensor. This helped them narrow their focus to a few mutated genes whose altered proteins seemed most likely to trigger immune system attacks. One of these mutated proteins, an altered form of spectrin-beta2, was present in all tumor cells that were attacked by the immune system and in none of the cells that were ignored.

Researchers cloned this mutant gene and put it into other mouse tumor cells that lacked the mutation. When transplanted into mice with normal immunity, the tumor cells that made the mutant spectrin-beta 2 protein were attacked and eliminated by immune cells.

"Many of the cancer genome projects now under way are looking for the 'driver' mutations, or the mutations that cause the cancers," Schreiber says. "Our results suggest there may be additional information in the sequencing data that can help us make the immune system attack cancers."

Schreiber calls the spectrin-beta2 mutation identified in the study "low-hanging fruit," noting that it's such a red flag to the immune system that its presence normally leads the immune system to assault cancer cells without any prompting from immunotherapy.

He and his colleagues are currently sequencing DNA in tumors grown from mice with normal immune systems to see if they can identify mutations that are not as readily discernible to the immune system.

"The idea would be to make a vaccine that helps the immune system recognize and attack six or seven of these mutated proteins in a cancer," he says. "Therapeutically, that could be very helpful."

The proliferation of metastases is often the main cause of complications and death from cancer. For the first time, researchers are looking very closely at the development of these metastases themselves, instead of focusing on the "primary" cancers from which they originated. In doing so, a team from the Swiss Center for Experimental Cancer Research (ISREC), at EPFL, was able to isolate a protein that plays a major role in metastasis development, and showed that the formation of secondary cancers could be prevented by blocking this protein. Their results were published December 7, 2011, in the advance online edition of the journal Nature and will open the door to new therapeutic options for treating late stage cancers.

A vital protein for metastases

The researchers already knew that cancer cells spread widely throughout the body once a malignant tumor is established. These cells don't always result in a secondary cancer, however. It turns out that all cancer cells aren't created equal: only some of them, known as "cancer stem cells," can initiate metastases. And in order to do this, they must settle into a spot - a niche - that is conducive for their development.

The ISREC team was able to show that several conditions are necessary for cancer to propagate. "In particular, we were able to isolate a protein, periostin, in the niches where metastases develop," explains Joerg Huelsken, holder of the EPFL Debiopharm Chair in Signal Transduction in Oncogenesis. "Without this protein, the cancer stem cell cannot initiate metastasis; instead, it disappears or remains dormant."

Minimal side effects in mice

Periostin exists naturally as part of the extracellular matrix, and has been shown to play a role in fetal development. In adults, it is only active in specific organs - the mammary glands, bones, skin and intestine. This research appears to prove that it plays an essential role in the environment that a cancer stem cell needs in order to develop a metastasis. Mice that were bred to lack this protein are resistant to metastasis formation. "We developed an antibody that adheres to this protein, making it inoperative, and we are hoping in this way to be able to block the process of metastasis formation," says Huelsken.

These experiments that blocked the periostin protein resulted in very few side effects in the mice. "This doesn't necessarily mean the same will hold true in humans," the researcher cautions. "We're not even sure that we'll be able to find an equivalent antibody that will work in humans."

This discovery is nonetheless very encouraging, especially since we now know that malignant tumors tend to spread more quickly than was previously believed. Preventing the development of metastases would thus appear to be an important therapeutic option that could limit the deleterious effects of cancers.

What is Cancer? What Causes Cancer?

Cancer is a class of diseases characterized by out-of-control cell growth. There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected.

Cancer harms the body when damaged cells divide uncontrollably to form lumps or masses of tissue called tumors (except in the case of leukemia where cancer prohibits normal blood function by abnormal cell division in the blood stream). Tumors can grow and interfere with the digestive, nervous, and circulatory systems, and they can release hormones that alter body function. Tumors that stay in one spot and demonstrate limited growth are generally considered to be benign.

More dangerous, or malignant, tumors form when two things occur:

1. a cancerous cell manages to move throughout the body using the blood or lymph systems, destroying healthy tissue in a process called invasion
2. that cell manages to divide and grow, making new blood vessels to feed itself in a process called angiogenesis.

When a tumor successfully spreads to other parts of the body and grows, invading and destroying other healthy tissues, it is said to have metastasized. This process itself is called metastasis, and the result is a serious condition that is very difficult to treat.

In 2007, cancer claimed the lives of about 7.6 million people in the world. Physicians and researchers who specialize in the study, diagnosis, treatment, and prevention of cancer are called oncologists.
What causes cancer?

Cancer is ultimately the result of cells that uncontrollably grow and do not die. Normal cells in the body follow an orderly path of growth, division, and death. Programmed cell death is called apoptosis, and when this process breaks down, cancer begins to form. Unlike regular cells, cancer cells do not experience programmatic death and instead continue to grow and divide. This leads to a mass of abnormal cells that grows out of control.

Genes - the DNA type

Cells can experience uncontrolled growth if there are damages or mutations to DNA, and therefore, damage to the genes involved in cell division. Four key types of gene are responsible for the cell division process: oncogenes tell cells when to divide, tumor suppressor genes tell cells when not to divide, suicide genes control apoptosis and tell the cell to kill itself if something goes wrong, and DNA-repair genes instruct a cell to repair damaged DNA.

Cancer occurs when a cell's gene mutations make the cell unable to correct DNA damage and unable to commit suicide. Similarly, cancer is a result of mutations that inhibit oncogene and tumor suppressor gene function, leading to uncontrollable cell growth.
Carcinogens

Carcinogens are a class of substances that are directly responsible for damaging DNA, promoting or aiding cancer. Tobacco, asbestos, arsenic, radiation such as gamma and x-rays, the sun, and compounds in car exhaust fumes are all examples of carcinogens. When our bodies are exposed to carcinogens, free radicals are formed that try to steal electrons from other molecules in the body. Theses free radicals damage cells and affect their ability to function normally.

Genes - the family type
Cancer can be the result of a genetic predisposition that is inherited from family members. It is possible to be born with certain genetic mutations or a fault in a gene that makes one statistically more likely to develop cancer later in life.

As we age, there is an increase in the number of possible cancer-causing mutations in our DNA. This makes age an important risk factor for cancer. Several viruses have also been linked to cancer such as: human papillomavirus (a cause of cervical cancer), hepatitis B and C (causes of liver cancer), and Epstein-Barr virus (a cause of some childhood cancers). Human immunodeficiency virus (HIV) - and anything else that suppresses or weakens the immune system - inhibits the body's ability to fight infections and increases the chance of developing cancer.
What are the symptoms of cancer?

Cancer symptoms are quite varied and depend on where the cancer is located, where it has spread, and how big the tumor is. Some cancers can be felt or seen through the skin - a lump on the breast or testicle can be an indicator of cancer in those locations. Skin cancer (melanoma) is often noted by a change in a wart or mole on the skin. Some oral cancers present white patches inside the mouth or white spots on the tongue.

Other cancers have symptoms that are less physically apparent. Some brain tumors tend to present symptoms early in the disease as they affect important cognitive functions. Pancreas cancers are usually too small to cause symptoms until they cause pain by pushing against nearby nerves or interfere with liver function to cause a yellowing of the skin and eyes called jaundice. Symptoms also can be created as a tumor grows and pushes against organs and blood vessels. For example, colon cancers lead to symptoms such as constipation, diarrhea, and changes in stool size. Bladder or prostate cancers cause changes in bladder function such as more frequent or infrequent urination.

As cancer cells use the body's energy and interfere with normal hormone function, it is possible to present symptoms such as fever, fatigue, excessive sweating, anemia, and unexplained weight loss. However, these symptoms are common in several other maladies as well. For example, coughing and hoarseness can point to lung or throat cancer as well as several other conditions.

When cancer spreads, or metastasizes, additional symptoms can present themselves in the newly affected area. Swollen or enlarged lymph nodes are common and likely to be present early. If cancer spreads to the brain, patients may experience vertigo, headaches, or seizures. Spreading to the lungs may cause coughing and shortness of breath. In addition, the liver may become enlarged and cause jaundice and bones can become painful, brittle, and break easily. Symptoms of metastasis ultimately depend on the location to which the cancer has spread.
How is cancer classified?

There are five broad groups that are used to classify cancer.

    Carcinomas are characterized by cells that cover internal and external parts of the body such as lung, breast, and colon cancer.
    Sarcomas are characterized by cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues.
    Lymphomas are cancers that begin in the lymph nodes and immune system tissues.
    Leukemias are cancers that begin in the bone marrow and often accumulate in the bloodstream.
    Adenomas are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.

Cancers are often referred to by terms that contain a prefix related to the cell type in which the cancer originated and a suffix such as -sarcoma, -carcinoma, or just -oma. Common prefixes include:

    Adeno- = gland
    Chondro- = cartilage
    Erythro- = red blood cell
    Hemangio- = blood vessels
    Hepato- = liver
    Lipo- = fat
    Lympho- = white blood cell
    Melano- = pigment cell
    Myelo- = bone marrow
    Myo- = muscle
    Osteo- = bone
    Uro- = bladder
    Retino- = eye
    Neuro- = brain

How is cancer diagnosed and staged?

Early detection of cancer can greatly improve the odds of successful treatment and survival. Physicians use information from symptoms and several other procedures to diagnose cancer. Imaging techniques such as X-rays, CT scans, MRI scans, PET scans, and ultrasound scans are used regularly in order to detect where a tumor is located and what organs may be affected by it. Doctors may also conduct an endoscopy, which is a procedure that uses a thin tube with a camera and light at one end, to look for abnormalities inside the body.Extracting cancer cells and looking at them under a microscope is the only absolute way to diagnose cancer. This procedure is called a biopsy. Other types of molecular diagnostic tests are frequently employed as well. Physicians will analyze your body's sugars, fats, proteins, and DNA at the molecular level. For example, cancerous prostate cells release a higher level of a chemical called PSA (prostate-specific antigen) into the bloodstream that can be detected by a blood test. Molecular diagnostics, biopsies, and imaging techniques are all used together to diagnose cancer.

After a diagnosis is made, doctors find out how far the cancer has spread and determine the stage of the cancer. The stage determines which choices will be available for treatment and informs prognoses. The most common cancer staging method is called the TNM system. T (1-4) indicates the size and direct extent of the primary tumor, N (0-3) indicates the degree to which the cancer has spread to nearby lymph nodes, and M (0-1) indicates whether the cancer has metastasized to other organs in the body. A small tumor that has not spread to lymph nodes or distant organs may be staged as (T1, N0, M0), for example.

TNM descriptions then lead to a simpler categorization of stages, from 0 to 4, where lower numbers indicate that the cancer has spread less. While most Stage 1 tumors are curable, most Stage 4 tumors are inoperable or untreatable.
How is cancer treated?

Cancer treatment depends on the type of cancer, the stage of the cancer (how much it has spread), age, health status, and additional personal characteristics. There is no single treatment for cancer, and patients often receive a combination of therapies and palliative care. Treatments usually fall into one of the following categories: surgery, radiation, chemotherapy, immunotherapy, hormone therapy, or gene therapy.
A.Surgery

Surgery is the oldest known treatment for cancer. If a cancer has not metastasized, it is possible to completely cure a patient by surgically removing the cancer from the body. This is often seen in the removal of the prostate or a breast or testicle. After the disease has spread, however, it is nearly impossible to remove all of the cancer cells. Surgery may also be instrumental in helping to control symptoms such as bowel obstruction or spinal cord compression.

B.Radiation
Radiotherapy treatment

Radiation treatment, also known as radiotherapy, destroys cancer by focusing high-energy rays on the cancer cells. This causes damage to the molecules that make up the cancer cells and leads them to commit suicide. Radiotherapy utilizes high-energy gamma-rays that are emitted from metals such as radium or high-energy x-rays that are created in a special machine. Early radiation treatments caused severe side-effects because the energy beams would damage normal, healthy tissue, but technologies have improved so that beams can be more accurately targeted. Radiotherapy is used as a standalone treatment to shrink a tumor or destroy cancer cells (including those associated with leukemia and lymphoma), and it is also used in combination with other cancer treatments.
C.Chemotherapy

Chemotherapy utilizes chemicals that interfere with the cell division process - damaging proteins or DNA - so that cancer cells will commit suicide. These treatments target any rapidly dividing cells (not necessarily just cancer cells), but normal cells usually can recover from any chemical-induced damage while cancer cells cannot. Chemotherapy is generally used to treat cancer that has spread or metastasized because the medicines travel throughout the entire body. It is a necessary treatment for some forms of leukemia and lymphoma. Chemotherapy treatment occurs in cycles so the body has time to heal between doses. However, there are still common side effects such as hair loss, nausea, fatigue, and vomiting. Combination therapies often include multiple types of chemotherapy or chemotherapy combined with other treatment options.
D.Immunotherapy

Immunotherapy aims to get the body's immune system to fight the tumor. Local immunotherapy injects a treatment into an affected area, for example, to cause inflammation that causes a tumor to shrink. Systemic immunotherapy treats the whole body by administering an agent such as the protein interferon alpha that can shrink tumors. Immunotherapy can also be considered non-specific if it improves cancer-fighting abilities by stimulating the entire immune system, and it can be considered targeted if the treatment specifically tells the immune system to destroy cancer cells. These therapies are relatively young, but researchers have had success with treatments that introduce antibodies to the body that inhibit the growth of breast cancer cells. Bone marrow transplantation (hematopoetic stem cell transplantation) can also be considered immunotherapy because the donor's immune cells will often attack the tumor or cancer cells that are present in the host.
E.Hormone therapy

Several cancers have been linked to some types of hormones, most notably breast and prostate cancer. Hormone therapy is designed to alter hormone production in the body so that cancer cells stop growing or are killed completely. Breast cancer hormone therapies often focus on reducing estrogen levels (a common drug for this is tamoxifen) and prostate cancer hormone therapies often focus on reducing testosterone levels. In addition, some leukemia and lymphoma cases can be treated with the hormone cortisone.
F.Gene therapy

The goal of gene therapy is to replace damaged genes with ones that work to address a root cause of cancer: damage to DNA. For example, researchers are trying to replace the damaged gene that signals cells to stop dividing (the p53 gene) with a copy of a working gene. Other gene-based therapies focus on further damaging cancer cell DNA to the point where the cell commits suicide. Gene therapy is a very young field and has not yet resulted in any successful treatments.
How can cancer be prevented?

Cancers that are closely linked to certain behaviors are the easiest to prevent. For example, choosing not to smoke tobacco or drink alcohol significantly lower the risk of several types of cancer - most notably lung, throat, mouth, and liver cancer. Even if you are a current tobacco user, quitting can still greatly reduce your chances of getting cancer.

Skin cancer can be prevented by staying in the shade, protecting yourself with a hat and shirt when in the sun, and using sunscreen. Diet is also an important part of cancer prevention since what we eat has been linked to the disease. Physicians recommend diets that are low in fat and rich in fresh fruits and vegetables and whole grains.

Certain vaccinations have been associated with the prevention of some cancers. For example, many women receive a vaccination for the human papillomavirus because of the virus's relationship with cervical cancer. Hepatitis B vaccines prevent the hepatitis B virus, which can cause liver cancer.

Some cancer prevention is based on systematic screening in order to detect small irregularities or tumors as early as possible even if there are no clear symptoms present. Breast self-examination, mammograms, testicular self-examination, and Pap smears are common screening methods for various cancers.