Mice with Kids’ Muscle Tumors Raise Hope for New Treatments

Oct. 14, 2004 – In a pair of new studies, University of Utah scientists took early but significant steps to fight a particularly deadly childhood muscle cancer by identifying some of the genetic events that cause the disease and then engineering mice that develop the tumors. The genetic events might be targets for new drugs that could be tested on the mice.

The disease, named alveolar rhabdomyosarcoma, “is a very mean childhood cancer,” says study leader Mario Capecchi, co-chair of human genetics in the university’s School of Medicine and an investigator with the Howard Hughes Medical Institute. “Once the cancer has spread, 80 percent of the children are likely to die within five years, even with the most aggressive treatment possible, including chemotherapy, surgery and radiation.”

Capecchi says the studies provide evidence that the cancer may originate in mature or nearly mature skeletal muscle fibers. That is controversial because satellite stem cells – cells that become new muscle – long have been suspected of giving rise to rhabdomyosarcoma.

“If we know where it starts and the cause, you might be able to prevent it, detect it early or develop new treatments based on a better understanding of the biology of the tumor,” says Charles Keller, a pediatric cancer specialist and first author of the studies.

During the past 30 years, “there have been dramatic improvements in cure rates for a number of cancers,” he adds. “However, the outcome for advanced alveolar rhabdomyosarcoma has remained largely the same for 30 years.”

Until now, scientists have been unable to breed mice with alveolar rhabdomyosarcoma, so “we understand the initiation and progression of this disease very poorly,” Keller says. “This work represents a significant step forward in the understanding of the disease, and puts us on the path toward new therapies” less toxic to patients and better aimed at the cancer.

Keller and Capecchi believe it still will take 10 to 20 years for new treatments to emerge. But, Keller adds, “After 30 years of limited progress, we have our foot in the door.”

The new studies will be published Nov. 1 in the journal Genes & Development, with one of the studies published online Oct. 15. The studies involved mice, which have a genetic makeup quite similar to humans and thus are used as “models” for study of human diseases.

Co-authors of the studies were University of Utah undergraduate Mark Hansen; Cheryl Coffin, a physician in pediatric pathology; Benjamin Arenkiel, a graduate student in human genetics; and Harvard Medical School’s Nabeel El-Bardeesy and Ronald DePinho.

A Mutant Fusion Gene’s Role in Muscle Cancer

Childhood cancers are rare because cancer is primarily age-related. The American Cancer Society says that out of 1.37 million new cancers in the United States this year, 9,200 would occur in children age 14 or younger, and 313 of those would be rhabdomyosarcomas.

The American Cancer Society says 78 percent of children with cancer survive at least five years. But Keller says five-year survival is a dismal 5 percent to 30 percent – depending on the group studied – among children with alveolar rhabdomyosarcoma, the most severe form of the disease. (Another form, embryonal rhabdomyosarcoma, is more responsive to treatment.)

Capecchi says the cancer causes tumors in various muscles throughout the body, primarily in the legs, arms and shoulders, but also in the back, neck, trunk and even the tongue.

Scientists already knew that 85 to 90 percent of children with alveolar rhabdomyosarcoma have an oncogene – a cancer-causing gene – named Pax3:Fkhr.

It is known as a “fusion gene” because it forms when two chromosomes each break into two pieces and then fuse or recombine. The fusion gene includes a piece of Pax3 – which plays a role in forming the muscles, nervous system and head – and piece of Forkhead of Fkhr, a gene that acts as a tumor suppressor to control cell division, which runs amok in cancer. Researchers believe Pax3:Fkhr causes cancer by triggering inappropriate muscle development.

Unraveling the Workings of a Cancer Gene

In their first study, the researchers probed how the Pax3:Fkhr fusion gene affected development of the mouse embryo, muscle formation in the embryo, and muscle growth that occurs after the mouse is born and satellite stem cells give rise to new muscle cells.

They engineered a version of the Pax3 gene that could be converted into a Pax3-Fkhr fusion gene at any stage of embryo development and in any desired cells – a new technology called “conditional mutagenesis.” Capecchi says these experiments revealed how the fusion gene turns various genes on or off, interfering with normal muscle development and providing clues to the complex series of steps by which the gene causes alveolar rhabdomyosarcoma.

“If you know the steps involved, then you can look at each of them and ask, ‘Are there drugs that would specifically interfere with that step,’” he adds.

Keller says muscles are made two ways. As an embryo grows, muscles develop from cells known as somites, which also give rise to bone and skin. Just before birth, muscle starts being made a second way: Muscles made earlier gain added mass because of satellite cells, which are stem cells destined to make muscle.

Rhabdomyosarcomas long were thought to arise in satellite stem cells. Yet when the researchers activated the cancer-causing Pax3:Fkhr gene in mouse muscle satellite stem cells, the embryos didn’t develop tumors. That makes satellite cells an unlikely source of the cancer.

Scientists who reviewed the paper argued the cancer could still originate in rare subtypes of muscle stem cells. Keller and Capecchi plan to test those cells. But Keller says that when the Pax3:Fkhr fusion gene was turned on in tens of thousands of satellite stem cells, those cells didn’t become cancerous, so it seems likely the gene must cause cancer by becoming active in some other type of cell.

In the second study’s key finding, mice developed muscle tumors much like the human cancer when Capecchi and Keller did two things. First, they activated the Pax3:Fkhr cancer gene in mature or nearly mature muscle fibers either late in development of mouse embryos or after the mice were born. Second, they inactivated either one of two tumor-suppressor genes – named Trp53 (or p53) and Ink4a/ARF – that normally control cell division.

Recent experiments show nearly all the mice develop muscle cancer when the scientists activate the Pax3:Fkhr cancer gene and deactivate either tumor suppressor gene, Keller says.

Mice previously have been created to develop the less deadly embryonal rhabdomyosarcoma muscle cancer, and a rare type, known as pleomorphic rhabdomyosarcoma, but until now, no mouse had developed the highly lethal alveolar rhabdomyosarcoma.

Capecchi says cancer specialists have believed alveolar rhabdomyosarcoma originates in satellite stem cells because the tumors proliferate after birth, when stem cells retain their ability to proliferate but mature muscle fibers normally do not. Also, a number of cancers involve stem cells. So “it’s a big deal for a [mature or nearly mature muscle] cell not be proliferating and then all of a sudden to be able to proliferate” to form tumors, Capecchi adds.

Keller says other researchers previously found that maturing skeletal muscle cells grown in the laboratory can revert to muscle stem cells. The Utah research found that tumors arising from mature or nearly mature muscle in mice have some characteristics of stem cells. That suggests the “primitive-appearing [rhabdomyosarcoma] tumors may be the result of non-primitive [muscle] cells reverting to a primitive state,” Keller says.

Mice with rhabdomyosarcoma now can be studied to determine how the cancer arises from mature or nearly mature muscle fibers, and also whether the Pax3:Fkhr fusion gene is required to maintain the cancer or just to get it started.

THE TREATMENT OF MUSCLE CANCER”

What Are the Normal Soft Tissues?

The human body is made up of individual“cells”, of which there are many various kinds. Initially, when the father’s sperm and mother’s egg join to form a fertilized egg, each cell in the fledgling human “embryo” is exactly the same. As the embryo’s cells divide, the genetic material within them, called“DNA”, instructs certain cells to “specialize”– that is become heart cells, lung cells, bone cells, brain cells, etc. This process of “specialization” is called “differentiation”, and accounts for the wide variety of cells making up adults. The early embryo separates cells into 3 basic distinctions– cells for making skin, brain and nerves (ectoderm), cells for making the organs (endoderm), and cells cells for making bone, flesh and blood (mesoderm). However, ultimately the “mesoderm” cells are found in all parts of the growing human. Certain specialized cells are programed to form “tissues”, which are a collection of cells for a certain purpose. Examples of tissues include skin, muscle, fat, bone, blood and cartilage. The tissues are joined in complex patterns to form“organs”, which contain many types of cells. For instance, the ear is an organ which contains bone (the “ossicles”), muscle fibers, nerves, fat, cartilage and skin, all precisely organized. Organs are further arranged into “organ systems” . The ear must be properly connected to another organ, the brain, to function. Other examples of organ systems include the skeletal, digestive, urinary, and reproductive systems. Still, as complex as the systems become, they still are made of single cells as the smallest unit of “life”.

The mature human body contains organs, bones, flesh, and blood, and we said that each of these complex structures are formed from simpler tissues. The“soft tissues” of the body are basically it’s flesh — formed of muscles, fat, cartilage, and fibrous tissues. These tissues are not only found as the“middle layer” (mesoderm) between the skin and bone, but are also a part of many internal organs, such as the stomach, bladder, and uterus, and bone. Thus, a disease of the “soft tissues” can actually arise almost anywhere in the body! This is because these basic tissues are the building blocks of nearly all a human’s “parts”. While the bone is initially from the mesoderm flesh (it starts out as cartilage), as it becomes calcified it is no longer considered a “soft tissue” (after all it is hard!). Thus, diseases, including cancer, of bone a classified separately from “soft tissue” diseases, even though the same tissues may be involved . Skin is also classified separately since it arises from a different area of the developing embyro (ectoderm), along with the nerves and brain.

Thus, the basic soft tissues making flesh in the adult are the muscle, fat, fibrous tissues (“sinews”), cartilage, and blood vessles. To understand disease of these, we must look at them on their cellular level. There are actually three types of muscle cells in the body, several types of fibrous cell, but only one type of fat and cartilage cell. The blood vessles are made up of layers of various types of cells. For muscle cells, there are “intercalated” heart cells (not discussed here) “striated” skeletal muscle cells, and“smooth” organ muscle cells.

You can see the range of crucial soft tissues in the body, and understanding the above prefixes allows one to categorize the diseases that arise from these “mesechy mal” cells. It is not uncommon for more that one type of cell to be involved with a disease process, so sometimes the names are conjoined together to describe the cells seen under the microscope. Examples include “Chondrofibro”, “Osteochondro” and “Lipofibro”; they are all “mesenchymal” (middle embryo layer) diseases.

What is Soft Tissue Cancer?

The “mesenchymal” or “soft tissues”, like all tissues, are made up of individual cells. Normally, cells within the forming body divide and grow very rapidly in the womb, in early childhood, and through puberty. In adulthood, new cells are only formed to replace those which have died from injury, old age or disease. The division of cells to produce new ones is under tight control by the “genes” within each cell. These genes are made up of DNA, and if it becomes damaged, that cell may start dividing out of control.Soft Tissue Cancer starts in a single cell which has become abnormal. This cells produces millions, and eventually billions, of copies of itself. The copies are called“clones” . These clones fail to function as normal body tissue, but instead divert resources from healthy cells to fuel their own growth. When there are about 1 billion cells, they form a clump, or “tumor” 1/2 inch across. A “tumor” merely means a swelling, it can be caused by infection, inflammation, cancer or whatever. If a tumor can only grow in it’s local area (even very large) but does not have the capacity to spread to distant body areas, it is called“benign” and isnot cancer. If, however, the tumor has the ability to spread to distant body areas, it is called “malignant” andthis is cancer. The actual process of spread is called“metastasis”, and can occur to any area of the body.

For benign Soft Tissue tumors, they are commonly given the suffix “oma” . The most common types of benign tumor are “Lipoma “ (from fat), “Leiomyoma “ (from smooth muscle) and “Fibroma “ (from fibrous tissue). These benign tumors may grow very large, but they will never“metastasize” (spread distantly) and so are not considered “cancer”. Simply removing them surgically should be curative, and if surgery is not practical then radiation therapy will often shrink them. Unless they are disturbing body function or cosmetic appearance, they often require NO THERAPY.

For malignant Soft Tissue tumors, they are commonly given the suffix“sarcoma” .This means a cancer that has arisen from the mesenchymal tissue, as opposed to “carcinomas”, which develop from the body’s lining tissues and organs. Any tumor that is called a “sarcoma” is cancerous, but not all cancerous mesenchymal tumors end with “sarcoma” . However, the common ones do, and include “Liposarcoma” (from fat cells), “Rhabdomyosarcoma” (from skeletal muscle cells), “Leiomyosarcoma” (from smooth muscle cells), “Fibrosarcoma” (from fibrous cells) and “Chondrosarcoma” (from cartilage cells). “Osteosarcoma” is the most common bone cancer, but is not considered a“Soft Tissue Sarcoma” and is discussed as a “Primary Bone Tumor”.

Other, rarer types of Soft Tissue Sarcoma (which may or may not have the word “sarcoma” in them) include “Angiosarcoma” (divided into Hemangiosarcoma and Lymphangiosarcoma– from blood or lymph vessels),“Hemangiopericytoma” (also from a blood vessel cell), “Mesothelioma ” (from abdominal or lung linings),“Synovial Sarcoma” (from joint linings), “Neurofibrosarcoma” (from nerve sheaths),“Kaposi’s Sarcoma (origin uncertain) and “Malignant Fibrous Histioctyoma” (from fibrous tissue). Some of the above are more aggressive than others, but they are all cancer!

How Common is Soft Tissue Sarcoma?

Each year in there about 8,000 new cases of “Soft Tissue Sarcoma” in the United States, which cause approximately 2,500 deaths per year. Thus, they represent ~1% of all new cancers. Soft Tissue Sarcoma is about 3 times more common than Bone Sarcoma. There are two “peaks” of most common patient age, one in childhood at 10 years old and the other in 40 year old adults. Thus Sarcomas are unlike the other major type of cancer, “Carcinomas” (e.g. breast, lung, prostate, colo-rectal) which all tend to get more likely as we age. Males and Females are overall equally affected by Sarcomas. In children, the most common type of Soft Tissue Sarcoma is “Rhabdomyosarcoma” (from skeletal muscle cells), which occur mostly in the Head and Neck areas. In adults, the most common type is now“Fibrosarcoma” or“Malignant Fibrous Histiocytoma”, which tends to occur in the trunk or extremities. In contrast to childhood cases, the least common area for adult sarcomas is in the Head and Neck area. Overall, the number of new cases of Soft Tissue Sarcoma has remained stable for the past 3 decades.

The common underlying factor is damage to “DNA” which causes the affected cell to become “transformed” — that is lose control over it’s division. Cancer is ultimately a disease of the DNA! The DNA is packed into thousands of “genes”, which are themselves located upon the 48 “chromosomes” (46 general plus 2 sex chromosomes) that all healthy humans have in every cell. The chromosomes become visible under an ordinary light microscope when cells divide, and nearly every case of Sarcoma shows chromosome damage. This damage usually includes pieces missing from chromosomes (“deletions”), or even parts of one chromosome getting stuck onto another (“translocations”). Overall, anything which can damage DNA, the fundamental genetic material, will increase the risk of a cell turning cancerous. This damage may be“latent”, meaning a cancer may arise many years or decades after the damage occurs.

Can Sarcomas Be Prevented?
There is no sure way to prevent sarcomas. It is always a good idea to avoid unnecessary exposure to potential carcinogens and avoid unwarranted X-rays. This is especially true for patients with family susceptibility to cancers, or who actually have genetic diseases. If a worrisome sign or symptom arises (see below) it should be evaluated promptly, and not ascribed to some benign process without proof. Eating a diet with enough vitamin C (“Ascorbic Acid”) is important for proper maintainance and healing of soft tissues. Vitamin C deficiency results in a breakdown of the soft tissues (“scurvy”), since it is essential for crosslinking their crucial collagen proteins. However, taking too much can also be harmful by causing the blood to become too acidic (“ascorbic acidemia”). A standard supplement multi-vitamin is well advised.

The human muscular system is incredibly engineered, providing for body support, movement, and the storage of sugar energy in the form of glycogen. There are 3 basic types of muscle in the body: Skeletal Muscle for voluntary movement, Smooth Muscle for involuntary processes like digestion, and Cardiac Muscle in the heart. Normally the muscles are a very trouble-free system, maintained by simple activity and exercise. Rarely, however, cancers called “sarcomas” arise from muscle. Smooth muscle gives rise to “myosarcoma”, and skeletal muscle to “rhabdomyosarcoma”.

It is crucial to get prompt diagnosis and proper treatment for a muscle cancer problem. This can make the difference between keeping or losing a limb, or even between life and death. Fortunately, recent advancements in therapy make limb loss less likely, and cure more like, than ever before. Understanding your options for a Muscle Cancer problem will give you the peace of mind of knowing you have done everything possible to help ensure a happy outcome.

CancerAnswers’ material explains, in plain English, the definition, types, frequency, risk factors, symptoms, evaluation, historic and latest effective treatment for Muscle Cancers. We tell you everything you must know to make the right choices today to deal with a Muscle Cancer problem.

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