BREAST CANCER CELL METASTASIS
- Bone Remodeling
- Bone Metastases Affects Remodeling
- Bone Loss and Fatty Acids
- Hormones and Metastasis
Breast cancer cells frequently metastasize to the bone, where they cause severe degradation of bone tissue. Metastatic cancer affects more than half of all women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcemia (abnormally high levels of calcium in blood plasma), and spinal cord compression. The bisphosphonates, including alendronate (Fosamax), tiludronate (Skelid), pamidronate (Aredia), etidronate (Didronel), risedronate (Actonel), ibandronate, and zoledronic acid (Zometa), are a class of drugs that protect against the degradation of bone, primarily by inhibiting osteoclast-mediated bone resorption (bone breakdown).
Bisphosphonates are analogs of a naturally occurring compound, called pyrophosphate, which serves to regulate calcium and prevent bone breakdown. Bisphosphonates are a major class of drugs used for the treatment of bone diseases as they have a marked ability to inhibit bone resorption. Bisphosphonates are considered standard care for tumor-associated hypercalcemia and have been shown to reduce bone pain, improve quality of life, and to delay and reduce skeletal events (Hortobagyi 1996; Roemer-Becuwe et al. 2003).Bone Remodeling
The renewal of bone is responsible for bone strength throughout our life. Old bone is removed (resorption) and new bone is created (formation). This process is called bone remodeling. Healthy bone is continually being remodeled. Two main types of cells are responsible for bone renewal: the osteoblasts involved in bone formation and the osteoclasts involved in bone resorption. There are several stages involved in bone remodeling. The first is activation. This process involves preosteoclasts that are stimulated and differentiated under the influence of cytokine and growth factors to mature into active osteoclasts. The next step is resorption, in which osteoclasts digest mineral matrix (old bone). The third step is reversal, which ends resorption and signals for the final phase, formation. During this stage, osteoblasts are responsible for bone matrix synthesis (collagen production). Two other noncollagenous proteins are also formed: osteocalcin and osteonectin, together they form new bone.Bone Metastases Affects Remodeling
In patients with bone metastases, bone resorption by the osteoclasts is increased and exceeds bone reformation. Calcium lost from the bones appears in increased amounts in the patient's blood serum and urine. This increase in bone resorption may result in pain, bone fractures, spinal cord compression, and hypercalcemia.
Normally, the activity of the osteoclasts and osteoblasts is well-balanced, with the osteoclasts cleaning out the fatigued bone and the osteoblasts rebuilding new bone. In metastatic cancer, there is - increased osteoclast activity caused by factors called osteoclastic activating factors (OAFs). These OAFs released by tumor cells and include parathyroid hormone-related peptide (PTHrP), growth factors, and cytokines.
Among the known inhibitors of osteoclast activity, the bisphosphonates are the most promising drugs available ( by prescription) to women with breast cancer who have a high risk of advancing cancer. Bisphosphonates interrupt the "vicious cycle" of bone metastases. Bisphosphonates inhibit bone turnover directly by decreasing resorption of bone and inhibiting the recruitment and function of osteoclasts.
Bisphosphonates may stop bone metastases from occurring if they are included at the onset of cancer diagnosis and treatment (ONI 2000). Bisphosphonates may delay the occurrence of bone metastases in women with breast cancer who do not have metastases.
In patients with bone metastases, bisphosphonates are useful as an adjuvant therapy to decrease bone pain, fractures, hypercalcemia, and progression of bone metastases (Delmas 1996). Treatment with bisphosphonates can also prevent the destruction of bone by cancer metastases and reduce the progression of metastatic tumors. A new bisphosphonate, risedronate, slows the progression of bone metastases in breast cancer patients, either by inhibiting the resorption of bone, which reduces the release of tumor growth factors, or by inhibiting the adhesion of breast cancer cells to bone matrix (Delmas 1996).
In women with early and advanced breast cancer and bone metastases the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy reduced bone pain, the risk of developing a fracture, and increased the time to a fracture (Pavlakis et al. 2002). Monthly infusions of pamidronate in 382 women with Stage IV breast cancer and bone metastases significantly reduced the incidence and prolonged the median time of skeletal complications (Hortobagyi et al. 1996).
Bisphosphonates are now third generation and are often used in the treatment of lytic bone metastasis. They inhibit the osteoclast activity that causes elevation of the blood calcium level and osteolytic bone weakening. Osteolytic holes form as the cancer degrades the bone, making it prone to fracture (Cristfanilli et al. 1999)., The bisphosphonates, zoledronate and ibandronate, manage tumor-induced hypercalcemia, Paget's disease of the bone, and multiple myeloma-associated bone resorption. These bisphosphonate drugs are three orders of magnitude more potent than the first-generation drugs etidronate, clodronate, and tilundronate. Patients newly diagnosed with lytic bone metastasis of breast cancer are offered bisphosphonate therapy, such as intravenous zoledronate or pamidronate every 3 or 4 weeks, as long as it proves effective. Oral clodronate offers equivalent results but is less well-tolerated.
Women with primary breast cancer who receive chemotherapy, hormone therapy, aromatase therapy, or oophorectomy may experience ovarian failure or early menopause, leading to a loss of bone mineral density.
The mechanisms by which tumor cells degrade bone involve tumor-cell adhesion to bone, as well as the release of compounds from tumor cells that stimulate osteoclast-induced bone degradation. Bisphosphonates inhibit cancer-cell adhesion and inhibit osteoclast activity. By preventing tumor-cell adhesion, bisphosphonates are useful agents for the prophylactic treatment of patients with cancer that is known to preferentially metastasize to bone.
There is evidence that growth factors, such as insulin-like growth factor and transforming growth factor, are released when the bone matrix is degraded. These growth factors could stimulate tumor-cell proliferation throughout the body and mayactivate cancer cells to the degraded bone ripe for clonal development, which may be a reason that early use of bisphosphonates significantly improved survival and may ward off metastasis.
Based upon the mounting research, it is strongly recommended that the use of bisphosphonates be considered at onset of breast cancer treatment to potentially stop bone metastases from developing. Patients are urged to discuss the use of bisphosphonates with their physicians.
Note: Administration of bisphosphonate therapy should be accompanied by an adequate intake of a bone supplement that supplies all the raw materials to make healthy bone. These include calcium, magnesium, boron, silica, vitamin D, and vitamin K. Do not take vitamin K with Coumadin or other anticoagulant drugs or blood thinners.Bone Loss and Fatty Acids
While people often use omega-3 fatty acids to reduce the inflammation associated with arthritis, these fatty acids may actually help prevent bone loss. French researchers found in a group of 105 patients that high levels of pro-inflammatory omega-6 fatty acids were strongly associated with bone loss. However, the use of omega-3 supplements--360 mg a day of eicosapentanoic acid (EPA) and 240 mg a day of docosahexaneoic acid (DHA) - appeared to decrease production of pro-inflammatory prostaglandin E2 in bone and significantly stopped bone loss (Requirand et al. 2000).Hormone Therapy and Metastasis
In primary breast cancer the estrogen receptor (ER) status represents an important prognostic factor and therefore, has a profound impact on the type of therapy employed. Yet, there is little research into the ER expression of disseminated breast cancer cells even though these cells are the main targets in adjuvant therapy.
A small pilot study involving 17 patients evaluated the ER expression profile on disseminated epithelial cells in bone marrow, one of the preferential organs for manifestation of distant metastases in breast cancer. Eleven patients (64.7%) were found to have ER-positive primary carcinomas. Of those eleven, only two patients revealed ER-positive epithelial cells in bone marrow. Additionally, one of these two patients expressed both ER-positive and ER-negative epithelial cells in bone marrow. Although in both of these cases the ER-positive epithelial cells in bone marrow derived from ER-positive primary tumors, in this small patient cohort none of the prognostic ally relevant clinical and pathological factors tested (i.e., TNM-classification, grading, and ER status in primary breast cancer) correlated with the ER status in bone marrow. A striking discrepancy between ER expression in primary breast cancers and the corresponding disseminated epithelial cells in bone marrow was found. This suggests either the selective dissemination of ER-negative tumor cells into the bone marrow or a negative impact of the bone marrow microenvironment on epithelial ER expression. While further research is required before conclusions can be drawn, this phenomenon might influence therapeutic effects of anti-hormonal treatment (Ditsch et al. 2003).OTHER CONSIDERATIONSDiet
Cancer has an appetite for sugar and requires sugar for survival. Sugar plays an active role in reducing the immune response and energizes cancer, as tumors are primarily obligate glucose metabolizers.
There is a relationship between lactic acid, insulin, and angiogenesis. In tumors, hypoxic conditions occur through both inflammation, which reduces blood flow, and the chaotic development of blood vessels within tumors. These hypoxic conditions alter the pathways by which immune cells and tumor cells burn fuel (glucose) for energy, creating excessive lactic acid. In an oxygen-rich (aerobic) environment, glucose is burned in an efficient process that produces a maximum amount of energy and a minimal amount of lactic acid. However, tumor cells in chronic hypoxic conditions produce excessive lactic acid and inefficient utilization of glucose. Thus, there is a vicious cycle in which the reduced energy output stimulates the tumor cells to burn more glucose, which in turn produces more lactic acid. Tumor cells consume glucose at a rate three to five times higher than normal cells, creating a highly stimulated glycolysis (glucose-burning) pathway.
This glucose consumption can waste the cancer patient's energy reserves, and the increased production of lactic acid can stimulate increased production of angiogenic factors. The macrophage-mediated angiogenesis creates a complex interplay between opposing regulators. Insulin plays an active roll in promoting angiogenesis. Insulin is a growth factor that stimulates glycolysis and the proliferation of many cancer-cell lines through tyrosine kinase growth factors (Boyd 2003). In cancer patients, elevated levels of insulin are common in cancerous tissue and blood plasma. Obesity, and early stages of Type-II noninsulin-dependent diabetes mellitus (NIDDM), has been implicated as risk factors in a variety of cancers.
Based upon cancer's sugar dependency, a sugar-deprivation diet is strongly recommended. An effective tool in eliminating sugar from the diet is through following the Glycemic Index. The index is a list that rates the speed at which foods are digested and raise blood sugar levels. The ratings are based upon the rate at which a measured amount of pure glucose affects the body's blood sugar curve. Glucose itself has a rating of 100, and the closer a food item is to a rating of 100, the more rapidly it raises blood glucose levels. Foods with a low Glycemic Index, such as vegetables, protein, and grains, are suggested (please refer to the Obesity protocol for specific information about low glycemic foods).
With regard to depleting sugar from the diet, the following should be considered:
- Limit or avoid all white foods, including (but not limited to) sugar, flour, rice, pasta, breads, crackers, cookies, etc.
- Read labels. Sugar has many names (brown sugar, corn syrup, honey, molasses, maple syrup, high-fructose corn syrup, dextrin, raw sugar, fructose, polyols, dextrose, hydrogenated starch, galactose, glucose, sorbitol, fruit juice concentrate, lactose, brown rice syrup, xylitol, sucrose, mannitol, sorghum, maltose, and turbinado, to mention only a few).
- Limit all fruit juices; per glass they contain the juice of many pieces of fruit and a large amount of fructose (fruit sugar) but no fiber. Instead, infrequently eat low glycemic-rated fruit in small portions.
Natural compounds have also been reported to inhibit the cancer-promoting effects of insulin. For example, vitamin C has been reported to increase oxygen consumption and reduce lactic acid production in tumor cells. In addition, some natural compounds may help reduce insulin production by reducing insulin resistance. Insulin resistance occurs when cells are no longer sensitive to insulin and thus more insulin is produced in an effort to reduce glucose levels. Insulin resistance has been implicated as a risk factor for breast cancer, and diets high in saturated fats and omega-6 fatty acids promote insulin resistance. Although the exact pathway is unknown, it is thought that the mechanism of action is via chronic activation of PKC. Some of the known natural compounds that can reduce insulin resistance include omega-3 fatty acids, curcumin, flavonoids, selenium, and vitamin E.
As discussed earlier in the protocol, estrogen is a growth factor for most breast cancers. High-fat diets and associated increases in fat tissue can increase estrogen availability in a number of ways:
- Fat tissue is a major source of estrogen production in postmenopausal women. Therefore, there is an association between high body weight and decreased survival in breast cancer patients.
- Obesity and possibly insulin resistance can decrease the levels of sex hormone binding globulin (SHBG) in both men and women and increase breast cancer risk or cancer progression. This is an important factor in estrogen-dependent breast cancer cells because it is adequate levels of SHBG that act as an anti-proliferative and provides an anti-estrogenic effect.
- Obesity can alter liver metabolism of estrogen, allowing the retention of high estrogen byproducts with high estrogenic activity within the body.
- High-fat diets may reduce the amount of estrogen excreted in the feces. In contrast, low-fat/high-fiber diets can reduce circulating estrogen.
Another consideration when discussing diet and breast cancer is the reduction of dietary estrogen. Several foods contain naturally occurring hormones (found in animal sources); synthetic hormones that can mimic estrogen in the human body (found in commercially packaged meat, poultry, and dairy products); or naturally estrogenic properties that can encourage the body's production of estrogens (natural foods such as soy). Regardless of the source, try to avoid all commercial animal products (including, but not limited to, meats, poultry, and dairy). Also avoid the use of soft plastic food-storage products that can give off large amounts of polymers (e.g., by leaching into food contents), thought by environmentalists and some researchers to be a possible cause of breast cancer.
In order to reduce estrogen, a breast cancer patient should consider increasing dietary intake of fish high in omega-3 fatty acids, whey, eggs, and nuts, occasionally including hormone-free poultry and hormone-free, low-fat dairy products.BLOOD TESTING
Monthly blood tests should include complete blood chemistry, with tests for liver function and serum calcium levels, prolactin, parathyroid hormone, and the tumor marker CA 27.29 (or CA 15.3). Additional blood tests to consider are the CEA and GGTP tests. These tests monitor the progress of therapies used and also detect toxicity from high doses of vitamin A and vitamin D3. The patient should insist on obtaining a copy of their blood workups every month.Continued
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