Part of what makes any cell mature (red blood cell, white blood cell, Mast cell) is the communication it gets from the surrounding environment.
When mast cells are developing, they normally mature in tissues at sites that they are programmed to go to, sites of wound healing, and sites of allergic inflammation. When Mast cells mature in the bone marrow, it is because the cell thinks it is getting a signal telling it to become a mast cell. Many people with Mastocytosis have a mutation in KIT, which causes this errant signal. So finding mast cells in the bone marrow is abnormal, and is criteria for mastocytosis.
Systemic Mast Cell Disease: An Update. L. Afrin, MD.
However, unlike the case in allergic reactions, mast cells are rarely
seen to degranulate during autoimmune16 or inflammatory processes.17 The
only way to explain mast cell involvement in nonallergic processes would be
through “differential” or “selective” secretion of mediators18 without degranulation.
19 In fact, this may be the only way this ubiquitous and versatile cell
may regulate immune responses without causing anaphylactic shock.
Instead, mast cells can undergo ultrastructural alterations of their electrondense
granular core, indicative of secretion, but without degranulation, a
process that has been termed “activation,”20–22 “intragranular activation,”23
or “piecemeal” degranulation.24 During such processes, mast cells can release
many mediators selectively as shown for serotonin18 and
eicosanoids.28–30 Triggers include innate molecules, such as stem cell factor
(SCF), which releases IL-6.31–34 IL-1 can also stimulate human mast cells
to release IL-6 selectively through 40–80-nm vesicles unrelated to the secretory
granules (800–1000 nm).35 Corticotropin-releasing hormone (CRH) can
stimulate selective release of VEGF without degranulation.36
Mast cells, both normal and abnormal, have a unique flow cytometric signature. These cells are brighter with their cell surface expression of CD117 by an order of magnitude than other cell in the human body. Under normal circumstances, they are always negative for CD25 and CD2. In the abnormal state, they sometimes can co-express CD25 and/or CD2 along with CD117, so if you’re going to do a bone marrow biopsy on a patient in whom you clinically suspect mast cell disease, you must send the aspirate for flow cytometry specifically for dual expression of both CD117 and CD25 or CD117 and CD2 and triple expression of CD117, CD25, and CD2.
These cells sometimes are CD68-positive as well. Many pathologists think more about macrophage or histiocyte disease when they see this signature and may not be aware that mast cells can also mark CD68-positive. If you find a patient to have a diagnosis that has been labeled as a histiocytic or macrophage disease, but it’s behaving more like a mast cell disease, you may need to go back to that pathology and run the additional testing looking to see if what had been described as macrophages or histiocytes might actually be mast cells.
Growth Factors: Jekyll and Hyde
These protein bosses can make cells go haywire, but they've also provided targets for new cancer patients
By Sue Rochman
The human body is a cellular factory with somewhere between 10 trillion and 100 trillion cell employees. Day in and day out, these cells participate in a complex manufacturing process that produces more than one trillion new cells every day. It's a complicated business that requires many rules and regulations to stay on track. To avoid anarchy, proteins called growth factors function as the supervisors of cell growth and tell cells when to divide. Factory rules govern exactly how a growth factor speaks to a cell: It must communicate through a special receptor—another protein—that sits on the cell's surface. Adding to the bureaucracy, a growth factor is not permitted to communicate with just any receptor. It can converse only with a receptor that speaks its specific language.
“Think of growth factors and growth factor receptors as a unit,” explains pathologist Michael Ittmann of the Baylor College of Medicine in Houston. “Growth factors are [proteins that] are secreted by the cell, and receptors are the proteins on the surface of the cell that bind to those growth factors.”
Growth factors (purple and yellow) bind to receptors (blue and green) that protrude from a cell's surface. A cross-section view shows how the opposite end of each receptor reaches the inside of the cell (deep red area). [Art: Nicolle Rager Fuller]
The first growth factor to be identified was a nerve growth factor discovered in the 1950s by the developmental biologist Rita Levi-Montalcini. In 1986, she shared a Nobel Prize with the American biochemist Stanley Cohen who, in the early 1960s, discovered a second growth factor, called the epidermal growth factor. Their work, which illuminated how the growth and differentiation of a normal cell is stimulated and regulated, also helped explain how cancer cells operate.
Over the past 50 years, researchers have discovered many more growth factors, some related to cancer. How many growth factors are there? “Too many to count,” says oncologist Amit Verma of the Albert Einstein College of Medicine in New York City.
“But what's important is that particular growth factors act only on specific cells.”
To send its message, a growth factor seeks out its partner receptor on a cell's surface. Growth factors and receptors are supposed to communicate only when the body needs more cells. But as in any factory, sometimes errors occur. In some instances a cell begins to produce too much growth factor, which can result in receptors transmitting too many growth messages to the cell. In other cases, genetic mistakes cause extra receptors to appear on a cell's surface, creating additional opportunities for the growth factors to communicate with the cell. This unsanctioned, unruly communication can lead to one of the hallmarks of cancer: uncontrolled cell growth.
By identifying this communication process, scientists exposed some of the inner workings of the cellular factory, enabling them to pursue the development of special agents—drugs—that could intervene and help the body regain control of its errant work force. As this research got under way, researchers realized that the best approach was to block the receptor, not the growth factor. If you block production of the growth factor, the body may respond by “starting to churn out more and more of it,” says Verma, defeating the drug's purpose. “It's easier to block the receptor, because there are only a certain number of receptors a cell can make.”
These protein bosses can make cells go haywire, but they've also provided targets for new cancer patients
By Sue Rochman
But easier does not mean easy. It's been a long road from the identification of growth factors to the development of drugs that interrupt their work. However, there have been some groundbreaking achievements. Herceptin (trastuzumab) was approved by the U.S. Food and Drug Administration (FDA) in 1998 for women with metastatic breast cancer whose tumors are of a type called HER2-positive. Identified more than a decade before Herceptin's approval, HER2 is a member of the HER family of receptors. (HER stands for human epidermal growth factor receptor.) Women whose tumors are HER2-positive have cells that contain too many copies of the HER2 gene, which helps cells grow, divide and repair themselves. Cells with these excess genes create too many HER2 receptors on their surfaces.
As a result, explains Verma, “even if there is only a small amount of growth factor in circulation, because the cell has more receptors, it divides more” than it should. Herceptin works by blocking the growth factor's ability to talk to the receptor. It's as if the growth factor gets a busy signal when it tries to call. This, in turn, keeps the cell from dividing.
More recently, Herceptin has also been found to significantly reduce breast cancer recurrence in women with early-stage HER2-positive breast cancer. Studies are now ongoing to see if the drug may also be effective in treating ovarian, bladder, salivary gland and endometrial cancer by blocking the HER2 receptor on these types of cancer cells.
Vascular endothelial growth factor (VEGF) has also attracted significant attention from researchers. VEGF binds to and stimulates receptors on cells that line the blood vessels, called vascular endothelial cells, and this effect is responsible for the development of new blood vessels—a process called angiogenesis. “When cancer grows, it needs blood vessels to feed it,” explains Verma. To ensure that it has these blood vessels, “cancer cells, or the cells around them, secrete VEGF.” The drug Avastin (bevacizumab) blocks the VEGF growth factor from binding to the VEGF receptor. In 2004, the U.S. Food and Drug Administration approved it for patients with metastatic colorectal cancer. Studies are now testing Avastin's effectiveness in treating renal cell carcinoma, malignant melanoma, brain tumors, and breast, bladder, ovarian and pancreatic cancers.
In the future, other growth factors may also become targets for new therapies that take advantage of our increasingly intimate understanding of how cells function. Ittmann's lab, for example, is studying fibroblast growth factors, which belong to a family of proteins that oversee the growth of a number of different types of cells, and are important in prostate, bladder and other cancers. Meanwhile, epidemiologist Jing Ma, at Harvard Medical School, is among those who are studying insulin-like growth factor (IGF). Ma has found that high IGF levels in the blood increases an individual's risk of developing colon cancer and prostate cancer. This research could lead to new ways of controlling growth factors to prevent cancer from occurring.
“A lot of the excitement in the field has been in showing that different kinds of cancer have a strong dependence on certain types of growth factors,” says Ittmann. “And if you can target that receptor using a [drug], then you have therapeutic potential.”
WANTED: MORE GROWTH FACTORS
Researchers' emphasis on keeping growth factors in check (see above article) might lead you to believe that you never want these receptors in overdrive. But that's not the case. There are times when people undergoing cancer treatment can benefit from an abundance of growth factors. The growth factor G-CSF, which is sold in synthetic forms under the names Neupogen (filgrastim) and Neulasta (pegfilgrastim), is given to patients during chemotherapy to stimulate the development of infection-fighting white blood cells. And patients take synthetic versions of the growth factor erythropoietin (EPO) to fight fatigue because it stimulates the development of red blood cells, which carry oxygen through the body. Right now, for treating cancer, says Amit Verma of the Albert Einstein College of Medicine in New York City, “These are two of the most important growth factors.”
*******Bacteria can also make histamine!
Bacterial HDC can also convert histidine into histamine, and bacterial infection of food can result in elevated levels of histamine, which can in turn cause food poisoning.
This is one reason why leftovers from a previous night's meal can sometimes be problematic for someone who has a mast cell disease. Even if week-old leftovers don't make the rest of the family sick, the person with IA or mastocytosis may end up in the bathroom with diarrhea.
What exactly does histamine do?
Cells have different kinds of receptors on their surfaces, each of which functions like a lock that can only be opened by a molecule or compound that has a particular design and particular biochemical qualities. Different receptors on the cell surface respond in different ways if they are “unlocked.” So if a substance can connect with a cell's receptors, it can bring about changes in that cell or its functioning.
Histamine exerts its effects on cells through four different kinds of receptors: H1, H2, H3, and H4. Reference. Only the first two are currently well understood. H1 and H2 receptors are involved in the changes that cause flushing, itching, increase in vascular permeability (third-spacing), changes in blood pressure, contractions or spasms of intestinal, bronchial and uterine muscles, increases in mucus production, increases in the rate of — and perhaps irregularity of — heartbeat, and increases in gastric acid production. Reference. So, diarrhea, flatulence, vomiting, stomach ache, low blood pressure, increased heart rate, and headache can all be due to high levels of histamine. Reference.
Fortunately, the effects of a given quantity of histamine are not effective for more than about thirty minutes. Unless more histamine is released, consumed or manufactured, the histamine in the body will be broken down fairly quickly. Reference.
Only 0.5% to 1.5% of histamine (in other words, approximately one percent) is excreted in urine. The bulk of the histamine is metabolized rapidly. Reference.
However, the metabolites from the breakdown of histamine may be found in a person’s urine for up to 24 hours after onset of anaphylaxis. Reference. These urinary histamine metabolites include N-methyl histamine and N-methyl imidazole acetic acid. Reference.