CANCER IN WILD ANIMALS

Introduction to Cancer in Wild Animals

Cancer seems to affect all animals, from anteaters to zebras.  Much less is known about the cancers that affect wild animals for the obvous reasons (they move around and may not be easily observed for long periods of time).  The cancers that have been studied are very interesting and may prove useful in the study of human cancer.  As an example, Tasmanian devils have a type of cancer that can be spread from animal to animal by biting!

Tasmanian Devil Facial Tumor Disease

In 2008, the International Union for Conservation of Nature officially declared the Tasmanian devil an endangered species

The animals were driven to extinction on the Australian mainland thousands of years ago, after humans introduced dingoes to the continent. The remainder of the wild population has since inhabited the Australian island-state of Tasmania.  In the mid 1990's the population reached an estimated 150,000 devils.⁽¹⁾ Today, however, the animals are plagued by an infectious cancer known as Tasmanian devil facial tumor disease (DFTD).  Since the emergence of the disease in 1996, the population has declined by more than 60%.⁽²⁾ As a result, what was once the largest surviving population of marsupial carnivores is now threatened with extinction.

This type of cancer is very unusual.  The great majority of cancer cases in humans and animals arise from a series of mutations in a single precursor cell and its daughter cells.  The process occurs over a period of years and does not involve contact with any other individuals.  DFTD develops differently.  It's transmitted from animal to animal and the cancer cells themselves are the infectious agent.

Researchers describe this phenomenon as allograft transmission .⁽³⁾   An allograft is the term for the transfer of cells/tissue from one individual to another.  An example in humans is organ transplantation.  The movement of cancer cells between animals has been confirmed by cellular and molecular studies.  A normal devil cell contains 14 chromosomes.⁽³⁾   DFTD tumor cells contain several very distinctive genetic changes and have only 13 chromosomes.  Importantly, the tumors from every animal tested appear identical.⁽³⁾  Researchers in Tasmania also found a devil with an unusual chromosomal abnormality in its non-tumorous tissue that did not appear in its tumor cells.⁽³⁾  These findings strongly suggest that the cancer did not arise from the animals' own cells. 

A cancer similar to DFTD occurs in dogs, and is known as Canine Transmissible Venereal Tumor (CTVT).  The immune system of dogs is capable of overcoming the disease, but devils do not seem to be able to do so.  Researchers have hypothesized that low genetic diversity among Tasmanian devils results in close kinship and reduces their immune responses.^{(4) (5) (6) (7)}   As a result, transplanted cancer cells are more likely to survive, grow, and spread.

Transmission can occur by biting, feeding on the same material, aggressive mating, and other social interactions.  DFTD tumors mostly form on the face and/or in the oral cavity.  The cancer can also metastasize to other areas of the body.  Nearly 100% of infected devils die within 6 months of the onset of clinical signs.⁽³⁾ Death results from an inability to feed, secondary infection, or symptoms associated with metastases. 

If researchers are able to develop a vaccine for DFTD, it could halt disease spread significantly.  Efforts are also being made to capture and relocate healthy animals to repopulate disease-free areas.  The Tasmanian government is working with conservation specialists to reduce the impact of the disease.

Shark Cartilage and Cancer: Overview

Shark cartilage has been used by many patients to complement traditional cancer treatments.   The effectiveness of the treatments is unclear.  Shark cartilage has not been approved by the FDA for the treatment of any disease, but it is available in the form of dietary supplements .⁽¹⁾ The use of shark cartilage in cancer treatment is based on the mistaken belief that sharks don't get cancer.  An extension of this belief is that shark body parts (i.e. cartilage) can prevent or treat cancer in humans.  However, benign and cancerous tumors can in fact develop in sharks; George Washington University Medical Center researchers reported over thirty tumors found in elasmobranchs, a group of animals that includes sharks, rays, and skates.⁽²⁾ The belief that sharks do not get cancer is not based on the known facts.

Another question that has been posed is whether or not sharks have reduced amounts of cancer.  This is a difficult question to answer because data concerning cancer rates in wild animals (including sharks) are limited, and the information that is available isn't conclusive.  There are some data which suggest that sharks may have a reduced occurrence of cancer.⁽³⁾  Some people interpret this to mean that sharks have some form of resistance to the development of cancer.  If sharks do have lower cancer rates, the reasons are not understood.

Why Cartilage?

The choice of cartilage, instead of some other body part is not random.  The first reason is the availability of the product.  The entire endoskeleton of sharks is composed of cartilage, amounting to about six percent of their body weight.⁽⁴⁾The amount of cartilage that can be obtained from a large shark is therefore quite large.  The second reason is based on some proven biology.  Cartilage, in both sharks and humans, lacks blood vessels.  It has been suggested that sharks resist cancer because of something in their cartilage that inhibits blood vessel growth (angiogenesis).  Angiogenesis inhibitors have been found in the cartilage of other animals.⁽⁵⁾

Growing tumors require angiogenesis to bring them oxygen, sugar and other nutrients.  Without a blood supply, tumors cannot grow beyond a very small size.  Blood vessels also serve as a "highway" for cancer cells to move to distant parts of the body (metastasize).  Angiogenesis inhibitors from other sources are already used to treat cancer patients.  If they exist, it is possible that the angiogenesis inhibitors in shark cartilage could be used create a drug to combat cancer in humans.  

Shark Cartilage and Cancer Cells in the Laboratory

Human studies with shark cartilage have been disappointing. Animal studies have provided some evidence to support its anti-angiogenic activity.  In one study, 0.6 grams cartilage/kilogram of body weight was administered to rats for 4.5 days.  Angiogenesis was then induced in the abdomen of the animals with chemicals.  The animals continued to receive the cartilage treatment for two weeks.  The results showed a notable decrease in blood vessel formation in the rats that had been fed shark cartilage compared with those that were not.⁽⁶⁾In another study, cancer cells were implanted into the corneas of rabbits.  A pellet of highly purified shark cartilage was placed next to the cancer cells.  After twenty days the tumors near to the cartilage showed reduced blood vessel development with zones of complete inhibition around the pellets themselves.⁽⁷⁾

Shark Cartilage and Human Cancer

Because of the results of shark cartilage in animals, several studies were performed in the late 1990's to examine the effectiveness of shark cartilage in treating cancer patients.  The results were disappointing.  In one study, twenty prostate or breast cancer patients received 1 gram/kg/day of an oral shark cartilage powder for twenty weeks.  Both survival times and quality of life were unchanged compared with a placebo control group.⁽⁸⁾   In another study, shark collagen was orally administered to sixty patients with different advanced cancers for six weeks.  The study noted no complete or partial responses.  The outcomes were similar to patients who had received only supportive care.⁽⁹⁾   Clinical trials with a shark cartilage extract, Neovastat® (AE-941), in patients with renal or lung cancer showed only limited or no benefit to patients.^(10) (11)

CANCER IN CAT

Introduction to Cancer in Cats

Cats are susceptible to a variety of cancers.  Among the most common are lymphoma, squamous cell carcinoma (skin cancer), mammary cancer, mast cell tumors, oral tumors, fibrosarcoma (soft tissue cancer) , osteosarcoma (bone cancer), respiratory carcinoma, intestinal adenocarcinoma, and pancreatic/liver adenocarcinoma.  The disease has become so prevalent that it is now the most common cause of death in cats.⁽¹⁾

Certain breeds are more prone to certain cancers than others.  Signs and symptoms differ depending on the type and stage of the cancer.  Detection and diagnosis requires some detective work.  Tumors that are visible and/or detectable by touch are most easily identified.   Vets often perform additional tests to make an accurate diagnosis.  Along with a physical exam, they may perform blood and urine tests, cytology, imaging and biopsies.

Treatment options vary and include surgery, chemotherapy, radiation, immunotherapy, photodynamic therapy, or a combination of these.  In many cases, cancer can be successfully treated.  Early detection and diagnosis is critical.  Regular visits to the veterinarian can help prevent and manage cancer. The American Veterinary Medical Association recommends twice-a-year wellness exams for all cats.⁽²⁾  Because the causes of cancer in cats are similar to those in humans, risk can be reduced by lowering the animal's exposure to harmful carcinogens, including tobacco smoke.⁽³⁾

Feline Leukemia and the Feline Leukemia Virus

Overview and Transmission

In humans, some viruses can lead to cancer. An example is human papilloma virus (HPV) which is the causative agent of most cases of cervical cancer. Viral infection can also lead to cancer in animals. Feline leukemia (FeLV; informally known as "Fee-Leuk") is an RNA virus (a retrovirus) that infects less than 2% of healthy, domestic cats in the U.S.^(1) (2) Infection is more prevalent in high-risk populations (i.e. cats with outdoor access and/or frequent social interactions).⁽¹⁾

The virus is spread from one cat to another via saliva, nasal secretions, feces, and milk.^(3) (4) It is transmitted during various forms of contact, from friendly grooming to not-so-friendly biting. The virus can also be passed to a developing kitten during pregnancy. The age and time of infection affect the progression and clinical outcome of the virus. Kittens are more likely to be infected and more likely to develop more severe complications.⁽⁵⁾ In most cases, FeLV initially infects lymphocytes in the back of the throat (oropharynx), which travel to the bone marrow, where virally infected cells are produced very rapidly.⁽⁶⁾

In most environments, the Feline leukemia virus cannot survive for long outside of the host. It can be "killed" with soap and disinfectants. At this time, studies show no evidence that FeLV can be transmitted from infected cats to humans.⁽⁷⁾ However, because FeLV positive cats may carry other diseases, infants, elderly individuals, and immunosuppressed individuals may want to avoid contact.

Symptoms

Infected animals may develop anemia, lymphoma, and other conditions. The FeLV-C subtype binds to and impedes the function of a heme transport protein on the surface of developing red blood cells. The result is a decrease in red blood cell numbers (anemia).^(8) (9) Signs of anemia in cats include paleness of the skin, tongue, gums, and mucous membranes surrounding the eye. FeLV- induced lymphomas are some of the most frequent tumors seen in cats. Symptoms depend on the location of the tumor, and may include weight loss, rough hair coat, loss of appetite, vomiting, diarrhea, respiratory distress, swelling of the lymph nodes and more. FeLV is also linked to diseases of the kidneys, joints, lymph nodes, small intestine, liver and nervous system. Depression of the immune system makes infected cats more susceptible to infections. As a result, they may be infected by organisms that healthy cats usually fend off. It is possible for FeLV positive cats to remain healthy. However, the prognosis is poor for cats with persistent active infection.⁽⁶⁾

Detection of FeLV

Veterinarians use several different laboratory tests to detect FeLV. These include 1) an antigen enzyme-linked immunosorbent assay (ELISA) and 2) an indirect immunofluorescent antibody assay (IFA). Both tests use blood samples to detect the presence of a protein that indicates FeLV infection. This protein is called p27, and is part of the structure of the virus.⁽⁶⁾ Inconclusive results may require additional testing with other methods, such as a specific type of polymerase chain reaction (PCR), which can detect FeLV DNA in infected animals.

Treatment for FeLV Infection

Currently there is no cure for FeLV. However there are a number of things that pet owners can do to manage FeLV positive cats, as recommended by veterinarians and experts:

• Visit the vet every 6 months for a physical examination, complete blood count, urine analysis, and other tests
• Carefully monitor the cat's health (i.e. measure and record weight loss)
• Provide cat(s) with a healthy and balanced diet. Avoid uncooked meat and eggs, as well as unpasteurized dairy products to prevent food-borne infections
• Confine cats to indoor environments to reduce exposure to harmful organisms

Antiviral therapy has been used in FeLV positive cats, but the effectiveness of the drugs is limited and they can be toxic. Medications to control and restore the immune system (immunomodulators) are also used. However data to support the proposed health benefits of these agents are limited.^(5) (7)

Prevention of FeLV Infection

Infection with FeLV can be prevented by vaccination. The vaccine is classified as non-core, which means it can be considered optional. However both the American Association of Feline Practitioners (AAFP) and the European Advisory Board on Cat Disease (ABCD) recommend that all cats with uncertain FeLV status and/or are at risk of exposure be vaccinated. Kittens are often vaccinated at 8-9 weeks of age and again at 12 weeks of age. Research shows that the vaccine will confer immunity for up to 1 year. Many vets recommend a booster vaccination 1 year after initial vaccination and annually thereafter. Because cats become less susceptible with age, some vets consider vaccination every 2-3 years sufficient for older animals.⁽⁶⁾

Feline Squamous Cell Carcinoma

Introduction
Squamous Cell Carcinoma (SCC) is a cancer that occurs in cats and dogs.  The tumors can appear many places but are seen most commonly on and around the eyes, ears, nose, mouth, and areas with little hair. 

Risk Factors/Detection/Staging
The primary cause of SCC is sunlight over-exposure, which is especially harmful to fair-haired cats. Age and exposure to cigarette smoke also increase the risk for SCC.⁽¹⁾  At first, SCC tumors look much like other common skin irritations, making them difficult to identify.  Scabs, hair loss, irritated skin, loss of teeth with limited healing, and raised red bumps on the skin are all possible sign of SCC.⁽¹⁾  Crusty sores can appear and develop into deep ulcers that bleed when irritated.  In later stages, the cancer may spread to the lymph nodes and lungs. Staging of the cancer may involve chest X-rays and testing lymph fluid.⁽²⁾    In advanced cases, SCC tumors can cause tissue death and destroy bone structure, leading to pain, discomfort, and possibly death.

Treatment
Several treatment options exist for SCC and they may be combined to increase success.  As with other cancers, the earlier SCC is detected, the more likely the treatment will be successful.  Tumors in the lower jaw or upper ear can be surgically removed.  Vets attempt to preserve as much healthy tissue as possible.  For tumors in the lower jaw, vets can perform a surgical Mandibulectomy, in which they attempt to remove the cancerous area(s).  The amount of the jaw tissue and bone removed depends on the tumor.  Possible side effects include difficulty eating and grooming, drooling, and poor appetite.⁽¹⁾  Despite a cancer reoccurrence rate of 38% and post-operation complications, one survey revealed that over 80% of owners whose cats had surgery would choose this treatment again.⁽¹⁾
Chemotherapy alone has not proven effective, but there is evidence that it may be effective when combined with other treatments.  A combination of the chemotherapy agent mitoXANTRONE  with external beam radiation therapy gave better results than either treatment option used alone.⁽³⁾   If the tumor is in the mouth, radiation should be considered with caution as it can cause severe inflammation.  Side effects may prevent normal eating and require the use of a feeding tube. 

Cryotherapy or freeze-surgery involves insertion of a probe that freezes the tumor, killing the cancer cells.  Cryotherapy is an option for tumors under 1 cm (about 0.4 inch) in diameter.  The rate of reoccurrence is high for larger tumors.⁽⁴⁾   Cryotherapy is a good option for tumors on the upper ear because the position allows for direct and aggressive treatment. 

Photodynamic therapy (PT) is a newer treatment option for Squamous Cell Carcinoma, and is not available everywhere.  This type of treatment involves putting a light-sensitive material in the tumor and exposing the tumor to a specific wavelength of light.  This causes the light-sensitive chemical to become active and destroy the tumor cells.⁽⁵⁾   It can be used repeatedly and with other treatment options.⁽⁶⁾ The side effects include swelling, redness, sensitivity to light, and death of healthy tissue around the tumor site.  A recent study followed 12 cats with SCC that were treated with PT.  Researchers found that when used alone, PT resulted in shrinkage of shallow tumors of the nose and ear, but had little effect on deeper tumors.  When used in combination with surgery, two cats exhibited a partial response to therapy, and one exhibited a complete response.⁽⁵⁾

Feline Mammary Cancer

Introduction
Feline mammary cancer (FMC) is the third most common cancer in female cats.  It is very uncommon in males, but cases have been reported.⁽¹⁾   The mammary gland tumors that result from FMC can be benign or malignant.  However, research shows that 80-96% of mammary tumors are malignant, meaning that they can invade nearby tissues, and are capable of metastasis (spreading to distant parts of the body).^(1) (2)  Unfortunately malignant mammary tumors tend to be much more harmful.

Cats have four mammary glands on each side of their body, any of which can be affected by FMC.  They are referred to as axillary, thoracic, abdominal, and inguinal glands.  These glands are the sites of primary tumor growth.  As with breast cancer in women, FMC is highly metastatic.   As a result, this type of cancer can spread to the lungs, the lining of the lungs and chest cavity (pleura), liver, regional lymph nodes, and other parts of the body.

Genes that have been targeted in human breast cancer research have also been studied in feline mammary cancer.  HER-2/neu is the gene that encodes the human epidermal growth factor receptor (type 2) protein.  This protein resides on cell surfaces, where it can interact with growth signals.  If gene amplification creates extra copies of the HER-2 gene, then its corresponding protein will also be overexpressed.  This is thought to lead to increased cell proliferation.  HER-2 overexpression has been detected in up to 30% of human breast cancer cases.⁽¹⁾   Similarly, it occurs in 30% of feline mammary cancer cases.⁽³⁾

Risk Factors/Detection/Staging
While all feline breeds may be affected by FMC, some are at a higher risk than others.⁽³⁾   Studies have shown the Siamese breed to have twice the risk of developing this type of cancer.^(1) (4)   Risk increases with age up to 14 years, with an average age of tumor development between 10 and 11 years.^(1) (2)   Early spaying reduces risk.  According to one study, intact females are 7 times more likely to develop mammary tumors than cats that are spayed at a young age.⁽⁵⁾   The latest age at which spaying  effectively reduces FMC risk has not been determined.

FMC is most often detected when pet owners or veterinarians feel a mass during examination of the mammary region.  However masses can also indicate other conditions, such as severely inflamed lesions, cysts, follicular tumors, and others.⁽³⁾   Histology can be used to confirm the diagnosis and classify the lesion.  Tumors are graded as well differentiated, moderately differentiated, or poorly differentiated, based on the appearance of the tissue/cells under a microscope.

Veterinarians and researchers agree that tumor size is the most important prognostic factor in FMC cases, affecting the progression of the disease and the survival time.⁽³⁾   In general, larger tumors have a worse prognosis.  Lymph node involvement and degree of metastasis also determine the severity of FMC cases.

Treatment
Surgical removal of mammary tumors is the most common treatment choice.  This may include nodulectomy (removal of one or more cell clusters), partial or complete removal of the affected mammary gland(s), removal of lymph nodes, and mastectomy (removal of all glands on the affected side(s)).  Veterinarians may use radiation or chemotherapy in addition to surgery.  Drugs used to treat FMC include 5-fluoroucil, doxorubicin, cyclophosphamide, methotrexate, prednisone, and vincristine.⁽⁶⁾  It has been shown that cats that respond to doxorubicin-cyclophosphamide treatments survive for longer periods of time.⁽⁶⁾

CANCER IN DOGS

Cancer in Animals -  Animals other than humans get cancer and this section examines a few types of cancer in domesticated and wild animals.

Introduction to Cancer in Animals

   

Humans aren't the only ones affected by cancer. This section contains information detailing cancer in animals. If the animal/cancer type in which you are interested is not yet presented, please check back because we will be adding new information regularly!

Cancer in Pets

According to the American Veterinary Medical Association (AVMA), cancer causes almost 50% of deaths in pets over the age of 10. Some common types of cancers in pets include: skin, breast, head and neck, lymphoma, leukemia, testicular, abdominal, and bone. Of the two most common household pets, dogs tend to get cancer at a higher rate than cats.⁽¹⁾

Cancer in Wild Animals

Cancer also occurs in wild animals. Some well documented examples of cancer in wild animals include facial tumors in Tasmanian devils,⁽²⁾fibropapillomatosis in sea turtles,⁽³⁾ and genital carcinoma in sea lions.⁽⁴⁾

Introduction to Cancer in Dogs

According to the Texas A&M University College of Veterinary Medicine, "Dogs have 35 times as much skin cancer as do humans, 4 times as many breast tumors, 8 times as much bone cancer, and twice as high an incidence ofleukemia."⁽¹⁾

Other common types of cancer found in dogs include cancer of the mouth, lymphoma, testicular and abdominal tumors.⁽²⁾

Canine Transmissible Venereal Tumor

Overview and Transmission
Cancer in humans is practically never transmitted from one person to another. Only very rare documented exceptions exist, usually involving surgical mishaps. Sticker's Sarcoma or Canine Transmissible Venereal Tumor (CTVT) is a very unusual form of cancer affecting canines (i.e. dogs). CTVT is transmitted by mating, licking, or other direct contact.⁽¹⁾ The tumor affects the genitalia and forms cauliflower- like mounds. In some cases the urethra becomes blocked making it difficult for the affected animal to urinate.⁽²⁾ If the cancer is located at the mouth and nose, nosebleeds, facial swelling, and nostril discharge are common symptoms.

Many human cancers are caused by viruses, including the human papilloma virus (HPV), a major cause of cervical cancer. Infection with viruses can lead to changes in normal cells within the infected person and lead to the development of cancer. CTVT is different! In this case, the cancer cells themselves are transmitted from animal to animal. Once in the new animal, the tumor can grow and eventually be spread to additional animals.⁽³⁾ Experiments have shown that CTVT is not transmissible via killed tumor cells or by cell's liquids.⁽¹⁾ Virus is usually present in the cell's liquid contents; if the liquid contents do not transfer CTVT then this is evidence that viruses are not responsible for the cancer. Also, all tumor cells examined so far have a molecular "fingerprint" in their DNA that is absent in normal cells. Specifically, the cancer cells contain a DNA sequence called Line-1 inserted near the oncogenes c-myc.⁽⁴⁾

Researchers have compared tumor DNA and normal DNA within different breeds of dogs. The results showed the expected differences between the normal cells' DNA, but all tumor DNA samples were very similar despite being from very different dogs. These results support that it is the tumor cells themselves that transfer CTVT between animals.⁽³⁾ In most cases, the immune system detects and eliminates cells of other types that are introduced into an animal (or human). This does not happen with CTVT. Upon the initial infection, CTVT begins a state of rapid and intense growth that lasts anywhere from three to nine months and possible longer in old or weakened dogs.⁽¹⁾ This is usually followed by a variable regression phase.

Treatment for CTVT Infection
Treatment choices for CTVT include surgery, chemotherapy, or radiation therapy. Chemotherapy is often very effective, usually resulting in complete remission. Surgery does not have a similarly high success rate.⁽⁵⁾Because the cancer is transmitted between animals and across generations, the cancer itself is thought to be very old! CTVT is thought to be anywhere from 200-2500 years old and represents the longest line of unbroken replications of a mammal's body cell. Aside from domesticated dogs, it is also transmissible to coyotes, foxes, jackals, wolves and immuno-suppressed mice.^(1) (6)

Canine Osteosarcoma

Introduction

Osteosarcoma (OSA) is a cancer that develops within bones.  It is often invasive and metastatic.⁽¹⁾   OSA is relatively rare in small domesticated animals, accounting for only 5-6% of canine malignancies.⁽²⁾   However, it is by far the most common primary bone tumor in dogs, accounting for 80% of cases.^(2) (3)

The diagram above highlights some of the bones affected by canine osteosarcoma.   This type of cancer occurs most commonly in the appendicular skeleton, including the radius and ulna, femur, tibia, scapila, humerus, and paw bones (phalanges).  The front limbs (forelimbs) are more likely to be affected than the rear (hind) limbs.  OSA also occurs in the axial skeleton, including the spinal bones, skull, jaw bone (mandible), and the vertebrae at the base of the spine (sacrum).  In rare cases, it can affect extraskeletal tissues, such as muscle.^(2) (3)  Because of its ability to metastasize, OSA can spread to other parts of the body.  Studies have shown that OSA invades the lungs in approximately 17% of cases.⁽³⁾

Risk Factors/Detection/Staging

Osteosarcoma is more common in adult dogs.  Large animals, weighing from 44 to 88 lbs (20 to 40 kg), are at a higher risk than smaller animals.⁽³⁾   

Signs of OSA in dogs include impaired movement due to pain and stiffness.  Affected dogs will often limp to avoid putting weight on the tumor-afflicted bone.  They also present with abnormal bone growth and swelling. 

Large tumor size is associated with poor prognosis.⁽⁴⁾  The location of the tumor can also affect the outcome of the disease.  Axial skeletal OSA and appendicular OSA tend to have similar prognoses.⁽⁵⁾   Tumors in the humerus bone tend to have a poor prognosis while tumors in the jaw tend to have better outcomes.⁽⁴⁾⁽⁵⁾

Treatment

Limb amputation is the standard treatment for OSA tumors located in the limbs.  Analgesics such as morphine are used to relieve pain, and most dogs can walk within 12-24 hours after the surgery.  Many dogs are able to adapt to the amputation within one month.  Interestingly, studies have shown that an owner's positive attitude can speed the adaptation process.⁽⁶⁾   Possible post-surgical complications include infection and recurrence of OSA in the stump.

Certain conditions can make dogs bad candidates for amputation, including arthritis, obesity, neurological problems and large breed.  For this reason, vets will perform limb-sparing surgeries, in which they remove the tumor and leave the surrounding tissue and bone intact.  This surgery has a higher rate of post-operation infection and OSA recurrence than amputation.  Studies reveal that the most common reason vets are asked to perform limb-sparing surgery is not based on the animals condition.  Rather, it is that owners are reluctant to proceed with amputation.^(7) (8)

Vets can use radiation as a curative treatment or to reduce pain and make the animal more comfortable (palliative care).  This type of therapy can reduce inflammation and heal micro-fractures.  Studies show that 70% of dogs respond positively to radiation therapy and experience pain relief.⁽²⁾

Chemotherapy drugs such as doxorubicin, carboplatin, cisplatin, or a combination of these drugs may also be used.  Chemotherapy alone has not been shown to extend survival time.  OSA-affected dogs treated with surgery and chemotherapy tend to survive longer.⁽⁹⁾

Unfortunately, despite the treatment options available, the prognosis for canine osteosarcoma is poor.  The estimated survival time is 6 to 12 months from the time of diagnosis, regardless of the treatment used.⁽¹⁾  The most common cause of death (or euthanasia) is disease spread (or metastasis).⁽⁷⁾

Canine Hemangiosarcoma

Introduction
Hemangiosarcoma (HSA) is a cancer that originates in cells that form blood vessels.  HSA is responsible for approximately 7% of canine cancer cases. In fact, it is more common in dogs than any other species of animal examined!⁽¹⁾

HSA occurs most commonly in the spleen, skin, and the right atrium of the heart.⁽²⁾  Primary tumors have also been reported in the lung, aorta, kidney, oral cavity, muscle, bone, urinary bladder, prostate gland, vagina, lining of the abdominal cavity (peritoneum), intestine, tongue, and the membrane that covers the white part of the eye (conjunctiva).⁽³⁾  HSA is highly metastatic, meaning that it frequently spreads.  When HSA is confined to the skin, it is less apt to spread.  Veterinarians estimate that over 80% of all other cases have already metastasized at the time of diagnosis.⁽³⁾

HSA cells may release proteins that stimulate the growth of new blood vessels. This process is known as angiogenesis, and is critical for tumor formation.  The presence of numerous blood vessels helps supply growing tumors with nutrients and oxygen and may serve as a "highway" for the cancer cells to metastasize to distant parts of the body.

Risk Factors
Older animals are at higher risk for developing hemangiosarcoma.  Affected dogs are usually diagnosed between 9 and 12 years of age.⁽⁴⁾  HSA tends to affect large breed animals more often than smaller ones.  Breeds that are more prone to this type of cancer include German Shepherds, Golden Retrievers, Labrador Retrievers, Pointers, Boxers, English Settlers, Great Danes, Poodles, and Siberian Huskies.  Breeds with short hair, light hair, light skin, and/or less pigmentation (i.e. Whippets) are more prone to hemangiosarcoma of the skin^{(5) (3) (6)}

Detection/Symptoms
Symptoms of HSA vary depending on the location and stage of the cancer, but may include weakness, weight loss, increased heart rate (tachycardia), abnormally fast breathing (tachypnea), abdominal swelling, lethargy, and paleness of mucous membranes.  Episodes of acute weakness and/or collapse may indicate that a tumor has ruptured, causing uncontrolled blood loss.  If internal bleeding occurs and the blood is reabsorbed from the body cavity back into blood vessels, the animal may gradually recover.  In more severe cases, tumor rupture can cause sudden death.⁽³⁾

Veterinarians often detect HSA during physical examinations.  They also use blood tests, urine analysis, chest x-rays, abdominal ultrasound, ultrasound of the heart (echocardiogram), tissue samples (biopsy), and more.  One type of blood test, the complete blood count (CBC), can detect anemia, misshapen or fragmented red blood cells, and other signs of HSA.  Some tests can even indicate the organ(s) being affected by the disease.  A blood smear that shows an increased number of immature red blood cells (normoblasts) may indicate cancer of the spleen.⁽³⁾

Treatment
Surgery is the standard treatment for dogs with HSA.  In one study, researchers from Colorado State University attempted surgery on 76 animals with HSA (66 dogs and 10 cats). In 42 cases, surgeons were able to remove the tumor(s) completely, leaving no visible cancer behind.  Following surgery, all 42 of these animals remained healthy for at least 12 months.  In the remaining 34 cases, the animals experienced incomplete tumor removal and/or other complications, resulting in worse clinical outcomes.  These findings confirm that complete tumor removal is the most significant prognostic factor for this type of cancer.  Researchers also found that certain tumors (i.e. eye or skin) were much easier to remove than others (i.e. bone or muscle).⁽⁷⁾

Veterinarians can use other methods to treat and manage hemangiosarcoma, but their effectiveness is limited.  Chemotherapy can be used in addition to surgery.  Research has shown doxorubicin to be the most effective chemotherapy drug for this type of cancer.  Despite treatment, the survival time for HSA-affected dogs typically does not exceed 6 months.  Death often results from metastasis to the lungs and other parts of the body.⁽¹⁾

Canine Mast Cell Tumors

Introduction
Mast cell tumors, also called mastocytomas, are the most common skin cancer in dogs.⁽¹⁾  Mastocytomas develop most often in dogs seven and a half to nine years of age, but can occasionally be found in dogs as young as four to six months.⁽²⁾  Different breeds also have different rates of mast cell tumors.  Boxers and Boston terriers have the highest rates.⁽²⁾

Mast cell tumors originate from mast cells, immune system cells found in many tissues of the body.⁽³⁾   Because mast cells can be found almost anywhere, mastocytomas have the potential to appear in all different regions of the body.  They are most commonly located on the skin on hind legs, the region between the neck and abdomen (thorax), or genital regions.⁽⁴⁾    Mast cells contain a variety of biologically active substances, including histamine, heparin, serotonin, and prostaglandins.  These chemicals are released from the cells during an allergic reaction.⁽⁵⁾   These are the substances that cause the symptoms associated with allergies: redness, itching, swelling, blood pressure drops, tearing, nausea, wheezing, ect.  Normally these chemicals are highly regulated, but when mast cells become cancerous they no longer appropriately control the release of the chemicals. 

Risk Factors/Detection/Staging
The unregulated release of chemicals by a mastocytoma can cause a variety of symptoms.  The symptoms any particular dog shows is variable, but can include vomiting, ulcers, bloody excrement, abdominal pain, and blood-clotting difficulties; gastro-intestinal problems are the most common signs.⁽⁶⁾ Mastocytomas appear as raised lumps that are often irritated or red in appearance.  Unfortunately, mast cell yumors have no characteristic form or color and are impossible to identify without laboratory testing.⁽¹⁾   Often when a mastocytoma is touched the skin becomes red, itchy, and swollen.^(7) (2)    This response is also called Darier's Sign .  It occurs because when the mast cells in the tumor are compressed they release the chemical histamine, and this causes irritation of the skin.

Although normal mast cells are typically fairly stationary, advanced mast cell tumors may spread (metastasize) to other places in the body.  Veterinarians classify (stage) mast cell tumors using a six tiered system (stages 0 to 5) based on the extent that the cancer has spread in the body.⁽¹⁾  Staging takes into account the number and size of tumors, lymph node involvement, and recurrence rate.⁽¹⁾  A higher stage indicates greater body involvement with Stage 5 representing distant metastasis including bone marrow or blood involvement.⁽²⁾  Another classification system, the histological grade (values from 1-3), is based on the physical appearance of the cells in the tumor.  More abnormal mast cells/tissues are associated with a higher histological grade and have a higher possibility of being malignant.⁽²⁾

Treatment
Surgical removal of the tumor is the most common treatment for mastocytomas of intermediate and lower stages.  Healthy tissue up to about one inch (2-3 centimeters) around the tumor must also be removed to prevent leaving any cancerous mast cells behind. For more advanced stages surgery is still recommended, but is often combined with radiation therapy or chemotherapy.⁽²⁾   If surgery is not thorough enough to remove all cells, external beam radiation therapy can be used to kill the remaining cells.  External beam radiation may also be used to reduce the size of a tumor before surgery.⁽²⁾

THE IMMUNE SYSTEM

The Immune System - The immune system is involved in guarding our bodies from internal and external threats, including cancer.  Because of the important role of immune cells in preventing and possibly contributing to cancer, as well as the use of immune cells and products in treating cancer, the subject is treated here in detail.

Introduction to the Immune System

The immune system consists of a large number of different types of cells and proteins that function to distinguish between normal and abnormal cellular components and between 'self' and 'non-self'. As an example, when a thorn gets stuck in the body, the immune cells are able to recognized the thorn as a foreign object (i.e. 'non-self') and attack it. The same is true for bacteria, viruses or other organisms that can invade our bodies. A more subtle distinction between self and non-self occurs in the recognition of cancer cells by the forces of the immune system. The cancer cells are recognized and attacked because they differ from the normal 'self' from which they arose.

The cells and proteins of the immune system participate in two broad and somewhat overlapping types of immunity-Non-specific and Specific⁽¹⁾

The Innate Immune System

The innate immune system gets its name from that fact that we are all born with it already in place, and it changes little throughout our lives. This division of the immune system provides protection by recognizing general features of possible pathogens. For instance, barriers such as the skin block entry of many kinds of organisms. Similarly, cells of the innate immune response recognize general features of pathogens, such as the cell walls of bacteria. These cells do not distinguish within the various classes of pathogens. To use a military analogy, it would be like using the same type of missile to shoot at many different kinds of targets instead of having different missiles for different types of target. Macrophages, for instance, are cells that participate in the innate immune response by finding, eating, and killing many different types of bacteria. Natural killer cells (NK cells) are another type of immune cell that functions to eliminate cells that have become infected with viruses and cancer cells.⁽¹⁾

 There are several different components of the innate immune system.  While is it sometimes called 'non-specific' immunity, that is not really accurate.  The defenses presented below are geared toward specific kinds of living and non-living 'invaders'.  When an organisma or particle attempts to enter the body, there are several physical and chemical barriers that must be bypassed.  Our skin is a tough flexible shield that blocks many types of invaders.  The entry points to our body are protected by sticky mucus (i.e. mouth, nose,  anus, vagina) or wax (ears) that traps bacteria, dust and other particles.     Body secretions like the acid in our stomachs and proteins in saliva and tears also work to prevent entry.  Our hair keeps larger organisms from reaching our skin.  If an invading organism or particle (i.e. a thorn) do make it past these defenses, cells (produced in the bone marrow) like macrophages and neutrophils are waiting to attack the foreign object.

Roll your mouse over the graphic below to see some components of the innate immune system in humans.

The Acquired Immune Response

Specific or adaptive immunity is the second line of defense because it is initiated if the non-specific, innate immune response is unable to completely combat the invading pathogen. The two systems really overlap somewhat. As an example, proteins produced by cells of the adaptive immune system are present in secretions like tears that also contain proteins that are part of the innate immune system.

The adaptive response develops and changes over the course of our lifetimes and is thus also called acquired immunity. The cells and proteins of the adaptive immune response are highly specific for invading pathogens or abnormal cells within the body. This is in contrast to the broad spectrum activities of the components of the innate immune system.

Like our innate immune system, the specific immune response is composed of several different types of cells and the proteins that they produce. The main cells of the adaptive immune response originate in our bone marrow and mature at different locations in the body. The cells may float around in the blood stream or lymphatic system or take up residence in an organ or tissue. Two of the main cell types spend a significant amount of time in the lymphatic system and are known as lymphocytes. These two types of immune cells are called T cells and B cells. A major proteincomponent of the acquired immune system is the antibodies produced by B cells.⁽¹⁾

The specific immune response is an active system with four defining characteristics:

• Antigen Specificity-The cells and proteins of this system only recognize very particular protein fragments (peptides) on other cells or dissolved in body fluids
• Diversity in the number of peptides that can be recognized. The acquired immune system is capable of responding to an astounding number of different foreign proteins. The number of different proteins and organisms we encounter in our lifetime is enormous and the acquired immune system is able to generate a specific response against each one!
• Memory-A hallmark of the acquired immune response is that if the same foreign object is encountered again, the response is both more rapid and more intense. The system remembers the things it has encountered. This is accomplished by the generation of 'memory' cells that live for a long time, waiting for their chance to re-activate and lead the charge.
• Self:Non-Self Discrimination-The acquired immune system is able to recognize cells that have been altered in very minor ways and respond appropriately. An example of self:non-self discrimination is the rejection of an organ following transplantation. A kidney from one person may be recognized as 'non-self' by the recipient and destroyed. For this reason, transplant patients receive medications that lower their immune response.⁽¹⁾

Of importance to us: The genetic changes that make normal cells into cancer cells can also alter them in ways that can be detected by the immune system. 

The Lymphatic System

Once they are formed in the bone marrow, lymphocytes circulate in the body and reside in lymphatic tissue including lymph nodes and the spleen, where they search for and await contact with their target proteins. The lymphatic system is a system of vessels (tubes) that is present all throughout the body. Like the more familiar circulatory system, the lymphatic system carries fluid, proteins and cells of the immune system. Red blood cells are not found in the lymphatic system. The two systems (lymphatic and circulatory) are connected. The lymphatic system picks up fluid and cells from around the body and returns them to the circulatory system via ducts located in the neck/shoulder area. The fluid within the vessels is known as lymph.

Like smaller streams merging into rivers that ultimately flow into an ocean, small lymphatic vessels empty their contents into larger ones. The flow leads to collections of grape-like structures knowns as lymph nodes. Many cells in the immune system reside in the lymphatic system for much of their existence.

The lymphatic system is of great importance in cancer for several reasons:

• Cancer cells can spread (metastasize) by getting into the lymphatic system.
• Many cancer types are classified or staged by whether or not cancer cells can be found in lymph nodes close to the site of the original tumor. The logic is this: The lymphatic system is found all over the body so if cancer cells from a tumor have made it that far, they may also have traveled to distant locations.

Cells of the Acquired Immune Response

The main cells of the specific immune response are lymphocytes - B cells and T cells. All lymphocyte precursors originate in the bone marrow. The pre-B cells stay in the bone marrow to undergo further development, while the T cell precursors migrate to an immune organ located in the neck (the thymus) to further develop. In fact, T cells get their name from the thymus. For trivia buffs: B cells are named after an organ found in chickens (the bursa of Fabricius) where they were first studied. Humans do not have an equivalent organ.

Early in T cell and B cell development, developing cells that strongly react with normal cell proteins are removed from the system. In this way, the immune system ensures that the B cells and T cells do not kill normal body cells. If self-reactive T cells and B cells are not removed from the lymphocyte population, autoimmune diseases like lupus or rheumatoid arthritis may develop.

There are two classes of mature T cells:

• Helper T cells- These cells help other immune cells, including CTLs, macrophages and B cells, carry out their functions more efficiently.
• Cytotoxic T Lymphocytes (CTL)-(cyto=cell and toxic because they can kill) These are cells that are able to kill other cells, they are cellular assasins. They directly kill any cell that they recognize as abnormal, such as cells infected with viruses or cancer cells.

The immature T cells residing in the lymph nodes and spleen do not mature into full effector cells until an APC comes to them and shows them, or presents to them, a particular protein antigen. Once the T cell is notified by the APC that there are cells in the body expressing these abnormal proteins, the T cells mature and leave the lymph nodes and the spleen to circulate in the body and find the abnormal cells. When the T cells find the abnormal cells they are able to kill them. In the case of virus infection, killing the infected cell is a harsh but effective way to limit the production of the viruses within. Cancer cells may also be recognized and eliminated by cytotoxic cells of the immune system.

B cells are another critical component of the acquired immune response.  Like T cells, B cells are formed in the bone marrow.  The cells move out into the body to mature.  B cells are responsible for producing antibodies, proteins that recognize foreign objects that enter the body (viruses,bacteria, other proteins, etc.).  Different B cells can recognize different targets.  There are millions of different kinds of B cells in our bodies and our immune system can respond to a very large number of different 'foreign' targets.

The immune system functions as an effective surveillance system to eliminate abnormal cells and invading organisms from our bodies.

How the Immune System Sees the World

Our immune system constantly surveys our body checking for invaders, like bacteria and viruses. The system is also able to recognize when normal cells become altered such as cancer cells. Recognition of invaders or altered 'self' involves cooperation between different cells and is tightly controlled.

The exact steps involved in the generation of an immune response are slightly different depending on the type of threat (virus, bacteria, etc.) but in general, our cells recognize small parts of the target, usually protein fragments that are created by the digestion of a larger protein. For example, a bacterium that invades the skin via a wound may be recognized by the proteins on its surface.
A protein or other product (sugar, lipid, etc.) that can be recognized by the immune system and lead to the production of an immune response is known as an antigen.

Some immune cells, including macrophages and dendritic cells, are able to carry these proteins on their surface, like waving a flag! The fragments of proteins (antigens) are 'presented' to the B and T cells and cause those cells to become active. The cells that are able to present antigens are known, understandably enough, as Antigen Presenting Cells or APC.

Individual B cells and T cells each express a single type of receptor molecule on their cell membrane. They do have many copies of that receptor on their surface. These receptors are called B-cell receptors (BCR, or immunoglobulins) and T-cell receptors (TCR). Each of these receptors binds to just one very specific peptide (antigen) from an abnormal cell or foreign object. The expression of a single type of receptor ensures that each lymphocyte is specific for just one antigen. Unlike the cells of the innate immune response, lymphocytes can distinguish between very similar target molecules. There are enought different lymphocytes in the body to recognize more than one billion different peptides! This amazing diversity assures that there are cells that are able to recognize just about any target encountered in our lifetimes.

The specific immune response is divided into two parts, humoral and cellular immunity. Humoral immunity is dependent on the production of specific proteins known as antibodies. Antibodies are produced by B cells. These protein interceptors are are small Y-shaped molecules that circulate in blood and other body fluids. When an antibody bumps into its specific target (antigen) it binds tightly allowing the target to be destroyed or inactivated. Antibodies can

• Neutralize toxins
• Bind to viruses to prevent their entry into cells
• Bind molecules in the bloodstream leading to their clearance
• Mark the target for consumption by of the non-specific immune system
• Work with other proteins in the body to directly kill bacteria and parasites

TUMOR-HOST INTERACTIONS

Tumor-Host Interactions - There are many interactions between different cells in a tumor.  This section covers some of the key cell types and the ways that they influence the growth of a tumor.

Introduction to the Tumor-Host Interactions

Tumors are surrounded by resident non-cancerous cells, connective tissue, and extracellular matrix. These components are known as the tumor stroma or microenvironment. Within the past several years, it has become evident that the tumor microenvironment plays an important role in both tumor initiation and progression. Due to this new knowledge, researchers have begun to investigate treatments that target both the cancer and its surroundings.

Overview of the Tumor Microenvironment

Tumors are complex structures containing many different kinds of cells. For many years scientists focused their research on understanding thetransformation of normal cells to into neoplastic, or cancer, cells but spent little time studying other cells present within a tumor. However, within the past several years, it has become evident that other components of tumors, including resident non-cancerous cells (fibroblasts, endothelial cells), connective tissue, and extracellular matrix (ECM; components of tissues that provide structural support, such as proteins like collagen) are equally important both in tumor initiation (early development) and progression. Collectively, these components are known as the stroma. Many researchers prefer a broader term, the tumor microenvironment, instead of the stroma, as it encompasses infiltrating cells of the immune system (macrophages, lymphocytes) and cell free molecules (growth factors, proteases), in addition to the more or less permanent stromal components⁽¹⁾ As the role of the tumor environment in cancer has become better understood, researchers are hopeful that novel therapeutic agents can be developed that target not just cancer cells, but the environment around them. Drugs targeting both cancer cells and stromal components may be significantly more effective than those directed solely against cancer cells.

The components of the tumor microenvironment can be grouped into four categories: (1) cancer cells, (2) non-cancer cells, (3) secreted soluble factors, (4) and non-cellular solid material such as the ECM ⁽²⁾. The actual composition of the tumor microenvironment is highly variable, with differences seen between patients and often in different areas of the same tumor. The tumor microenvironment is often altered as the disease progresses; even the percentage of a tumor made up of cancer cells may change ⁽³⁾

Communication between a tumor and its surroundings is very important. Both pro- and anti-tumor interactions occur that act to enhance or block tumor formation/progression. For example, one critical molecule, transforming growth factor beta (TGF-Β), is a critical regulator of tumor progression. TGF-Β is a potent inhibitor of cell growth and is secreted by multiple cell types within the tumor microenvironment; however, mutations in many advanced carcinomas result in cancer cells that are unaffected by TGF-Β (meaning they continue to grow even in the presence of TGF-Β). In addition, tumors themselves often secrete TGF-Β, which reduces the growth of surrounding normal cells, thus allowing the tumor cells to reproduce rapidly without competition from neighboring cells ⁽¹⁾ In this way, tumors continue to grow at the expense of surrounding cells.

A Closer Look at The Stroma and Tumor Development

To examine the effect of the environment on tumor growth, rats were treated with a carcinogen to cause mutations. They were then given a drug to inhibit the growth of normal liver cells. Under these conditions, the only cells able to grow were those with mutations that allowed them to avoid the growth inhibitory effect of the drug (i.e. cancer cells). In rats given the carcinogen but not the growth inhibitor, no such cancer cells developed. This experiment demonstrated that tumors cannot grow when the surrounding tissue is normal; in other words, growth of a tumor from a single mutated cell can only occur when the stromal environment is altered in such a way to allow unrestrained tumor growth⁽⁴⁾

Conditions within the Tumor Microenvironment

The conditions within the tumor microenvironment differ considerably from those in normal tissue. Hypoxia (low oxygen levels), low pH (acidic conditions), and low glucose levels are common. In addition, massive cell death occurs, resulting in the release of proteins and other molecules into the surrounding environment. These factors may help or hurt tumor growth ⁽¹⁾ Hypoxia results in the generation of oxygen free radicals which lead to DNA damage (mutation). Mechanisms for repairing this damage are also less efficient under hypoxic conditions. The end result is an increase in the mutation rate and greater variation within the tumor population. Another result is that only those cells with mutations that allow them to survive in harsh conditions will continue to grow and contribute to the tumor ⁽²⁾

Importantly, the conditions within the tumor microenvironment do not affect cancer cells only. The normal cells surrounding a tumor exhibit altered characteristics compared to corresponding cells in normal tissue. These cells also develop mutations, and the tissue is often disorganized compared to normal tissue ⁽³⁾ These abnormal properties might arise in two ways. The conditions of the tumor microenvironment (hypoxia and low pH) may induce mutations, or soluble products (growth factors, cytokines) released from the tumor may alter the genes expressed by stromal cells ⁽¹⁾ Interestingly, mutations have been identified in the stroma of non-cancerous tissue collected from breast cancer patients, suggesting that pre-existing genetic alterations in the stroma may provide the foundation for tumor initiation ⁽²⁾Experiments have illustrated the importance of the stroma in tumor development.

A Closer Look at Tumor: Stroma Interactions

The influence of the tissues surrounding a tumor has been recognized for many years.  In 1976, to examine the effect of the environment on tumor growth, rats were treated with a carcinogen to cause mutations. They were then given a drug to inhibit the growth of normal liver cells and part of the liver was removed to provide a strong growth stimulus. Under these conditions, the only cells able to grow were those with mutations that allowed them to avoid the growth inhibitory effect of the drug (i.e. cancer cells). In rats given the carcinogen but not the growth inhibitor, no tumors developed. This experiment suggested that tumors cannot grow when the surrounding tissue is normal; in other words, growth of a tumor from a single mutated cell can only occur when the stromal environment is altered in such a way to allow unrestrained tumor growth.⁽⁴⁾

Inflammatory Cells and Cancer

The role of the immune system in cancer is a double-edged sword. While there is evidence that it can be beneficial (for example, immunosuppressed patients, or those with weak immune systems, have a higher incidence of cancer), in many cases the immune system clearly promotes tumor growth ⁽¹⁾ The role of immune cells in cancer is well documented. Innate immune cells (cells such as macrophages that do not produce antibodies but are capable of ingesting foreign organisms) are prominent in pre-malignant and malignant tissues, and are believed to contribute to tumor formation through the release of molecules that regulate cell growth and migration, alterations of the ECM, andangiogenesis ⁽²⁾ In addition, many cancers (gastric, cervical, colon, liver) are associated with infection and correlate with the activity of the normal host immune response. Chronic inflammatory conditions make people more likely to develop certain cancers; for example, patients with Crohn's disease have a higher incidence of colorectal cancer. A greater understanding of the ways by which the inflammatory response initiates cancer may lead to potent new cancer treatments ⁽¹⁾

In other cases the tumor itself attracts immune cells which can then impact tumor progression. Tumor cell damage and hypoxia attract macrophages from the blood into the tissue surrounding a tumor. In most cases, high tumor associated macrophage (TAM) counts are correlated with reduced survival. Many tumors secrete factors that prevent macrophages from alerting other immune cells to the presence of cancer cells, resulting in an inability of the immune system to recognize the tumor. Macrophages themselves secrete factors that enhance tumor cellproliferation, invasion, and promote angiogenesis. In addition, TAMs release oxygen free radicals and other mutagenic compounds that may create mutations in surrounding cells. The ability of TAMs to stick to tumor cells allows macrophages to carry tumor cells into the circulation and thus aid in the spread of the cancer (metastasis) ^{(3) (4) (2)}

Fibroblasts and Cancer

Fibroblasts are the predominant cells in the stroma. They are responsible for generating the ECM as well as connective tissue. Because each tissue has different requirements, fibroblasts from different organs express different genes. Changes in fibroblast behaviors are associated with tumor progression, mostly due to factors made by the tumor. Fibroblasts begin to express α-SMA (alpha-smooth muscle actin), which allows them to contract. These myofibroblasts are highly proliferative and are surrounded by a dense meshwork of the structural protein collagen. This profile is known as desmoplasia and is often associated with recruitment of immune cells and angiogenesis ^(1) (2)

Interestingly, although the behavior (phenotype) of fibroblasts is often altered by close proximity to a tumor, in other cases altered fibroblasts have been isolated from patients with no cancer, but who have hereditary predispositions to the disease. This observation suggests that these altered fibroblasts may actually aid in the development of cancer⁽³⁾ How might these cells become oncogenic in the absence of a tumor? Several possibilities exist, including exposure to carcinogens, accumulation of genetic damage due to aging, and hormone imbalances. Molecules present in healing wounds can also alter fibroblasts in such a way that they resemble fibroblasts found near tumors⁽²⁾

Matrix Metalloproteinases and Cancer

One of the most critical roles performed by fibroblasts, both in normal and cancer tissue, is the production and remodeling of the extracellular matrix (ECM). Not only does the ECM impart structural support and strength to tissues, it also provides attachment sites for cell surface receptors, and functions as a reservoir of cytokines and other growth factors⁽¹⁾ The structure of tumor-associated ECM is abnormal, with loose structure and disorganized collagen fibers⁽²⁾ Matrix metalloproteinases (MMPs) are a large family of enzymes capable of degrading components of the ECM and are critical in maintenance of the ECM. Degradation of the ECM by MMPs releases growth factors, enhances migration, and alters cell:cell and cell:ECM interactions⁽³⁾. Although MMPs can be produced by tumor cells, most are produced by fibroblasts and macrophages, and high levels of MMPs are found at the tumor:stroma interface⁽⁴⁾. Because MMPs are secreted into the surrounding environment by these cells, they are a good example of the interaction that occurs between a tumor and its environment.

Evidence indicates that MMPs are key players in multiple steps of tumor progression; they promote metastasis, angiogenesis, and even tumor initiation. One of the many paradoxes of MMP activity is that MMPs often have opposing effects depending on the composition of the tumor environment and the nature of MMPs present. For example, MMPs can either promote or inhibit angiogenesis, depending on the molecules they release from the ECM⁽⁵⁾ <⁽³⁾ Because of their potent effects on tumor formation and metastasis, several clinical trials attempted to use MMP inhibitors as anticancer therapy. However, these trials were soon stopped as patients developed muscle and bone pain, formed connective tissue nodules, and developed joint disorders. These trials highlight the difficulty of targeting molecules critical for the function of multiple tissues⁽⁵⁾.