Friday, July 18, 2014
Doctors and Future Doctors from all over the world
The links below as to connect to facebook of Doctors from all over the world
https://www.facebook.com/groups/DocsWorld/
https://www.facebook.com/WDoctors
https://www.facebook.com/medicalbooksplusmcqs/posts/608547949244132:0
http://www.meddybear.net/blog
Pulmonary Arterial Hypertensions in Infants
Sildenafil (viagra) in infants
Sildenafil in the treatment of pulmonary arterial hypertension in infants ...
Definition
Pulmonary arterial hypertension(PAH) is a progressive, and often fatal,
debilitating disorder.
The increased pulmonary artery
pressure found in PAH is due to disturbances in key vascular mediator pathways
including relative deficiencies of vasodilators such as nitric oxide (NO) and
prostacyclin, as well as exaggerated production of vasoconstrictors such as
endothelin and thromboxanes.
Symptoms
Progressive breathlessness, exertion limitation, frequent decline and
failure of the right ventricle.
Mechanism of action of sildenafil
Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5).
Present throughout the body, PDE5 is found in high concentrations in the lungs.
Inhibition of PDE5 enhances the vasodilatory effects of nitric oxide in
pulmonary hypertension by preventing the degradation of cyclic guanosine
monophosphate (cGMP), which promotes relaxation of vascular smooth muscle and
increases blood flow. In animal models and human trials, sildenafil has been
found to produce a relatively selective reduction in pulmonary artery pressure
without adverse systemic hemodynamic effects after 3 months of oral therapy.
Inhibition of PDE5 by sildenafil may also enhance the platelet antiaggregatory
activity of nitric oxide and inhibit thrombus formation.
Infant’s dose
The protocol for dosing was
(1) first dose of 1 mg/kg/dose within 30 minutes admission or within 12
hours of delivery (whichever earlier),
(2) Dosing every six hours for a
maximum of 8 doses,
(3) Dose was doubled if the
oxygenation index (OI) or SpO2 did not improve (If OI continued to be <10%
of previous value and SpO2 was not increasing >5 of previous value) and
blood pressure remained stable.
how can i prepare the infant's dose
from viagra tablet???
newborns received oral Sildenafil solution
through feeding tube which was prepared by crushing a 50 mg tablet of
sildenafil in distilled water or simple syrup to make a concentration of 5
mg/ml.
notes
At 2012The U.S.Food and DrugAdministration (FDA) is recommending that
sildenafil not be prescribed to children (ages 1 through 17) for pulmonary
arterial hypertension. This recommendation against use is based on a recent
long-term clinical pediatric trial showing that: (1) children taking a high
dose of sildenafil had a higher risk of death than children taking a low dose
and (2) the low doses of sildenafil are not effective in improving exercise
ability.
References
1)
Clavecilla SQ. New insights into the treatment of pulmonary arterial
hypertension. Formulary, 2003 Mar; 38(3): 150-4, 157-8, 160.
2) Mehta S. Sildenafil for pulmonary arterial hypertension: exciting, but
protection required. Chest. 2003 Apr; 123(4): 989-92.
3) Pfizer Inc. FDA Approves Pfizer’s Revatio as Treatment for Pulmonary
Arterial
Hypertension.http://www.pfizer.com/pfizer/are/news_releases/2005pr/mn_2005_0606.jsp#additional.
Accessed June 23, 2005.
4) Kataoka M, Satoh T, Manabe T, Anzai T, Yoshikawa T, Mitamura H, Ogawa S.
Oral sildenafil improves primary pulmonary hypertension refractory to
epoprostenol. Circ J. 2005 Apr;69(4):461-5.
5) Kanthapillai P, Lasserson T, Walters E. Sildenafil for pulmonary
hypertension. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003562.
6) Karatza AA, Bush A, Magee AG. Safety and efficacy of Sildenafil therapy
in children with pulmonary hypertension. Int J Cardiol. 2005 Apr
20;100(2):267-73.
7) Leuchte HH, et al. Hemodynamic response to sildenafil, nitric oxide, and
iloprost in primary pulmonary hypertension. Chest. 2004 Feb; 125(2): 580-6.
8) Chockalingam A, Gnanavelu G, Venkatesan S, Elangovan S, Jagannathan V,
Subramaniam T, Alagesan R, Dorairajan S. Efficacy and optimal dose of
sildenafil in primary pulmonary hypertension. Int J Cardiol. 2005 Mar
10;99(1):91-5.
9) Lee AJ, Chiao TB, Tsang MP. Sildenafil for pulmonary hypertension. Ann
Pharmacother. 2005 May;39(5):869-84.
10) Sastry BK. Clinical efficacy of sildenafil in primary pulmonary
hypertension: a randomized, placebo-controlled, double-blind,
crossoverstudyImage. J Am Coll Cardiol, 2004 Apr;43 (7), pp. 1149-53.
11) Ng J, Finney SJ, Shulman R, Bellingan GJ, Singer M, Glynne PA.
Treatment of pulmonary hypertension in the general adult intensive care unit: a
role for oral sildenafil? Br J Anaesth. 2005 Jun;94(6):774-7.
12) American Heart Association rapid access journal report. Impotence drug
may help children with fatal lung disorder.
06/23/2005.http://www.americanheart.org/presenter.jhtml?identifier=3031499.
Accessed: June 23, 2005.
National Heart, Lung, and Blood
Institute: "What Is Pulmonary Arterial Hypertension?" National Heart,
Lung, and Blood Institute: "Living with Pulmonary Arterial
Hypertension." WebMD Medical News:"Viagra Label May Note Rare Vision
Problems. “ViagraThe Associated Press.
Links
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Friday, August 31, 2012
Aloe Vera Plant Benefits
Aloe Vera is a succulent plant known for its healing, medicinal properties. For topical use, the leaf is sliced open and the pulp from within is used for application. Among the many forms it is used in, aloe vera juice and aloe vera gel are the most popular. Aloe Vera is often considered a wonder plant, and people claim its assistance in curing just about any ailment.
Aloe vera plant has the capacity to treat following ailments:
Constipation: Constipation is treated with orally consumed dried latex that is taken from the inner lining of aloe leaves. The laxative properties of a substance called aloin contained in the aloe vera plant, is supported by scientific evidence. A large number of herbal remedies that treat constipation contain aloe vera extracts.
Genital herpes: A few studies have suggested that Aloe vera extracts in a hydrophilic cream may be effective in treating genital herpes in men. This combination is believed to work better than aloe gel or a placebo.
Psoriasis vulgaris: The initial evidence suggests that psoriasis vulgaris may be effectively treated with an extract from aloe in the form of a hydrophilic cream. However, it is strongly recommended against it as additional research is needed in this area.
Seborrheic dermatitis: Seborrheic dermatitis causes stubborn dandruff and the skin on the scalp to become inflamed, scaly and itchy. Aloe vera lotion may be an effective treatment, according to initial studies.
Cancer prevention: Evidence suggests that aloe consumed orally may reduce the risk of developing lung cancer. However, it is unclear if it is the aloe itself or other factors that may provide this benefit.
Dry skin: Aloe vera plant health benefits have been extolled for decades. The moisturizing qualities of aloe, and its consequent capacity to effectively reduce skin dryness are backed by early, low-quality scientific evidence. To be sure of its healing powers, higher quality studies are required.
Lichen planus: This common skin disease results in an itchy, swollen rash on the skin or in the mouth. The scientific evidence suggesting that aloe may be a safe, helpful treatment for lichen planus, is limited. There is need for additional research.
Skin burns: Initial evidence form scientific investigations suggest that aloe may assist the healing of mild to moderate skin burns. Additional proof is required to confirm this fact.
Skin ulcers: Among the aloe vera benefits for skin is the likelihood of its ability to help heal skin ulcers with local application. These conclusions have been arrived at through early studies, which still leaves the need for high-quality studies comparing aloe alone with placebos.
Ulcerative colitis: While research regarding benefits of aloe vera in treating ulcerative colitis (UC) is limited, nonetheless, the results are promising. It is yet to be understood how aloe vera measures up to other treatments used for UC.
Wound healing: The results on aloe vera's wound healing properties are conflicting. While some studies say that it has a positive effect, others report that there are no improvements, and at times potential worsening of the condition. Further study is required to establish its exact effect.
Among the other therapeutic uses of aloe vera, it is said to sooth skin irritation caused by prolonged exposure to the sun's radiation. There is insufficient evidence to support claims of the use of aloe vera to treat mucositis, diabetes and HIV infection. Aloe vera juice benefits are often advertised with regards to treating heartburn and irritable bowel syndrome. It is also common practice for cosmetic companies to include extacts from Aloe vera in their products. While aloe vera plant proves to be extremely beneficial for the hair and the skin, to truly harness its powers, it is important to know how to use the plant. It is the transparent fluid exuded by the inner leaf wherever it is cut or crushed, that must be applied to the hair or skin, for it is this substance that is said to have soothing, moisturizing properties.
Aloe Vera for Cancer Treatment
Introduction
Aloe Vera is a soothing and sanative herbal medicine. Indigenous to West Africa, it is cultivated all over the world for its medicinal usefulness where it's used mostly for the treatment of skin diseases.
The herb aloe has more than 300 species, but the best known of them all is the 'Aloe Vera'. It is a short, stemless succulent plant with thick and fleshy stems. For the purpose of healing, it's used both internally and externally. Chemical compounds such as lectins, acemannan, polysaccharides and anthraquinones along with vitamin C, amino acids, germanium etc., make aloe vera very useful in the maintaining and toning of dry skin, repairing of blood vessels, liver, stomach, and kidney, and treat various disorders like diverticulitis, ulcers, asthma, and heartburn. It also helps in healing cuts and wounds. Many researchers claim that it has the power to help cure HIV/AIDS. However, recent research shows that it can also be used for the treatment of cancer too.
Aloe Vera and Cancer
Corrosion causes damage to the genes. These adducts multiply themselves in a cell (mitosis) and possess the power to damage that cell permanently. They are not initially recognized by the immune system. Hence, they keep on dividing in each cell and the possibility of cancer increases. At the time of mitosis, the cells make the same adducts. This is how cancer cells are produced. Though all the cells, except the nerve cells from the central nervous system, need to get replaced, it becomes impossible for the healthy neighboring cells to grow. Once the cancer turns malignant, it conquers the whole body of the host. This ability makes cancer the most life-threatening disease of them all. However, early detection of the disease combined with proper nourishment of the patient will help the person overcome the condition. This nourishment is done by growing the cells in a controlled body environment. This is termed as 'tissue culture'. Cancer treatment therapy, called 'Chemotherapy', entails a close examination of the cells. If found infected, they are killed immediately.
Aloe vera is proven to be useful in the treatment of cancer patients, for whom chemotherapy doesn't work. As it contains a little amount of the cancer-healing substance, it works its magic when used in conjunction with chemotherapy. Also said to have a good effect on the blood, aloe vera helps the absorption of vitamin-C and antioxidants, that's why it is speculated that it will increase the effectiveness of anti-cancer herbs.
How does it Help During Chemo?
The question frequently asked is does chemo really cure the patient of cancer? The answer often is Yes! However, at what price does the tumor vanish, doesn't the health and spirit of the patient itself also seem to vanish. So are we really treating the patient or are we treating just the tumor? More often than not it's the latter. Chemotherapy can't differentiate between the damaged and the healthy cells. So, healing from cancer as well as the chemotherapy, both become essential. The radiation from chemotherapy are sometimes too toxic for patients to survive. Aloe vera works as a soothing agent in patients undergoing the therapy. That's why alternative therapies always act as support medicines to enable the patient live through the rigorous chemotherapy sessions.
Effects on the Immune System
The presence of cancer according to some people suggests a weak immune system, because it is not able to react to the new growth of cells that it should ideally perceive as a threat due to their un-natural foreign nature. Hence, aloe vera works on the immune system in great degrees making it stronger so that it can eat away the cancerous cells. The unique mixture of aloe vera in aloeride works as the best cancer suppressor. It prevents cancer by suppressing the tumor causing cells. The aloeride is made up of aloe barbarensis miller, that has the same medical characteristics as the Aloe vera plant.
Besides enriching the immune system aloe vera is also a great detoxifier. The acemannan present in it promotes the production of lymphocytes and helper cells which prevent the infection from spreading to the healthy cells. The herb slows down the growth of cancerous tumors, as it contains lectins and emodines, which are two tumor resistant chemicals. It actually checks the growth of malignant tumors and also provides a soothing effect in patients suffering from skin cancer.
Availability
Aloe vera is not always used in its direct form, but also in the various forms available in the market, such as - gels, capsules, creams, and drinks (the most popular being filleting the flesh, removing the skin, and then blending the pulp to make it drinkable). All these products are chemically tested and certainly prove beneficial for the treatment of cancer. Though, aloe vera gels and creams are most popular.
Aloe Vera Juice
A regular intake of aloe vera juice helps to prevent the production of cancer cells in the body. For patients already suffering from cancer, it soothes intoxication caused by radiotherapy. The juice has proved helpful in healing many types of cancers, including breast cancer, ovarian cancer and blood cancer (leukemia).
Besides that it also helps the digestive tract function normally, which is a very important part of the human body and is responsible for a major portion of medical conditions that people experience. Basically, aloe vera proves useful in healing the side effects caused by chemotherapy and radiotherapy. Being a great anti-inflammatory it could indirectly help our body experience less stress while the anti-cancer treatment is underway, which as mentioned earlier is one of the greatest ordeals that is faced by a patient with cancer.
Aloe Vera Creams
These creams are odorless and are best used to reduce the itchiness of the skin in psoriasis (a type of skin cancer). It also protects the skin from the damage caused by the exposure of the skin to the ultraviolet rays, that are very harmful for cancer patients.
What we must understand though, is the amount of aloe vera extract that should be used. Aloe vera, though clinically tested, does contain a few substances that do not agree with a few people resulting in a few serious side effects like hepatitis, diarrhea, stomach pain, nausea, problems in blood clotting, thyroid problems and so on. You need to remember that the herb acts best as a supporting medicine and not as the sole cure for cancer. In conjunction with the proper treatment of cancer, it helps the body to receive the treatment better and improve on its effectiveness. However, you need to first check with your physician before starting out on an aloe vera supplement.
Corrosion causes damage to the genes. These adducts multiply themselves in a cell (mitosis) and possess the power to damage that cell permanently. They are not initially recognized by the immune system. Hence, they keep on dividing in each cell and the possibility of cancer increases. At the time of mitosis, the cells make the same adducts. This is how cancer cells are produced. Though all the cells, except the nerve cells from the central nervous system, need to get replaced, it becomes impossible for the healthy neighboring cells to grow. Once the cancer turns malignant, it conquers the whole body of the host. This ability makes cancer the most life-threatening disease of them all. However, early detection of the disease combined with proper nourishment of the patient will help the person overcome the condition. This nourishment is done by growing the cells in a controlled body environment. This is termed as 'tissue culture'. Cancer treatment therapy, called 'Chemotherapy', entails a close examination of the cells. If found infected, they are killed immediately.
Aloe vera is proven to be useful in the treatment of cancer patients, for whom chemotherapy doesn't work. As it contains a little amount of the cancer-healing substance, it works its magic when used in conjunction with chemotherapy. Also said to have a good effect on the blood, aloe vera helps the absorption of vitamin-C and antioxidants, that's why it is speculated that it will increase the effectiveness of anti-cancer herbs.
How does it Help During Chemo?
The question frequently asked is does chemo really cure the patient of cancer? The answer often is Yes! However, at what price does the tumor vanish, doesn't the health and spirit of the patient itself also seem to vanish. So are we really treating the patient or are we treating just the tumor? More often than not it's the latter. Chemotherapy can't differentiate between the damaged and the healthy cells. So, healing from cancer as well as the chemotherapy, both become essential. The radiation from chemotherapy are sometimes too toxic for patients to survive. Aloe vera works as a soothing agent in patients undergoing the therapy. That's why alternative therapies always act as support medicines to enable the patient live through the rigorous chemotherapy sessions.
Effects on the Immune System
The presence of cancer according to some people suggests a weak immune system, because it is not able to react to the new growth of cells that it should ideally perceive as a threat due to their un-natural foreign nature. Hence, aloe vera works on the immune system in great degrees making it stronger so that it can eat away the cancerous cells. The unique mixture of aloe vera in aloeride works as the best cancer suppressor. It prevents cancer by suppressing the tumor causing cells. The aloeride is made up of aloe barbarensis miller, that has the same medical characteristics as the Aloe vera plant.
Besides enriching the immune system aloe vera is also a great detoxifier. The acemannan present in it promotes the production of lymphocytes and helper cells which prevent the infection from spreading to the healthy cells. The herb slows down the growth of cancerous tumors, as it contains lectins and emodines, which are two tumor resistant chemicals. It actually checks the growth of malignant tumors and also provides a soothing effect in patients suffering from skin cancer.
Availability
Aloe vera is not always used in its direct form, but also in the various forms available in the market, such as - gels, capsules, creams, and drinks (the most popular being filleting the flesh, removing the skin, and then blending the pulp to make it drinkable). All these products are chemically tested and certainly prove beneficial for the treatment of cancer. Though, aloe vera gels and creams are most popular.
Aloe Vera Juice
A regular intake of aloe vera juice helps to prevent the production of cancer cells in the body. For patients already suffering from cancer, it soothes intoxication caused by radiotherapy. The juice has proved helpful in healing many types of cancers, including breast cancer, ovarian cancer and blood cancer (leukemia).
Besides that it also helps the digestive tract function normally, which is a very important part of the human body and is responsible for a major portion of medical conditions that people experience. Basically, aloe vera proves useful in healing the side effects caused by chemotherapy and radiotherapy. Being a great anti-inflammatory it could indirectly help our body experience less stress while the anti-cancer treatment is underway, which as mentioned earlier is one of the greatest ordeals that is faced by a patient with cancer.
Aloe Vera Creams
These creams are odorless and are best used to reduce the itchiness of the skin in psoriasis (a type of skin cancer). It also protects the skin from the damage caused by the exposure of the skin to the ultraviolet rays, that are very harmful for cancer patients.
What we must understand though, is the amount of aloe vera extract that should be used. Aloe vera, though clinically tested, does contain a few substances that do not agree with a few people resulting in a few serious side effects like hepatitis, diarrhea, stomach pain, nausea, problems in blood clotting, thyroid problems and so on. You need to remember that the herb acts best as a supporting medicine and not as the sole cure for cancer. In conjunction with the proper treatment of cancer, it helps the body to receive the treatment better and improve on its effectiveness. However, you need to first check with your physician before starting out on an aloe vera supplement.
Friday, April 27, 2012
Colon cancer stem cells
Colorectal
cancer (CRC) is the third most common form of cancer and the second cause of
cancer-related death in many industrialized countries and is characterized by a
heterogenic pool of cells with distinct differentiation patterns, leading to
655,000 deaths worldwide per year (1). Despite the emergence of new targeted
agents and the use of various therapeutic combinations, none of the treatment
options available is curative in patients with advanced cancer. A growing body
of evidence is increasingly supporting the idea that human cancers can be
considered as a stem cell disease. According to the cancer stem cell model,
malignancies originate from a small fraction of cancer cells that show
self-renewal and pluripotency and are capable of initiating and sustaining
tumor growth (2).
This
review will focus on the biology of normal and malignant colonic stem cells,
which might contribute to our understanding of the mechanisms responsible for
tumor development and resistance to therapy. First, we will briefly revise the
knowledge available on normal intestinal stem cells and recent advances in
understanding crypt biology, which have led to new theory on the origins of
colon adenomas and cancers. Then, we will summarize the evidence and current
status on colon cancer stem cells, focusing on their relevance and promises for
the treatment of colorectal carcinoma.
Colonic stem cell identification
The
adult colonic epithelium has a well-defined architecture organized into crypts,
dynamic structures which are constantly self-renewing (3). Each crypt unit is
maintained by adult multipotent stem cells (SCs), located at the bottom of the
structure itself, that are able to simultaneously self-renew and generate a
population of transiently amplifying cells which in turn generate more the
specialized intestinal epithelial mature cells. Three differentiated cell types
mediate the function of colonic epithelium: the colonocytes, also termed
absorptive enterocytes, the mucus-secreting goblet cells and the hormone-secreting
enteroendocrine cells (Figure 1).
Adult
SCs are defined by several key functional properties including: self-renewal,
potential for multilineage differentiation and tissue regeneration. Two
different models have been proposed to localize the intestinal SCs; the “+4
position” model and the “stem cell zone” model (4). According to the former,
the intestinal SCs are located at the +4 position relative to the bottom of the
small intestine crypt, just above the non-cycling Paneth cells. These cells are
quiescent, slowly cycling, label retaining cells (LRCs) and, through asymmetric
division, give rise to their differentiated progeny. The more recent “stem cell
zone” model states that active, rapidly cycling cells and self-renewal, termed
crypt base columnar (CBC) cells, are the true intestinal SCs (Figure 2). These cells are interspersed
between the Paneth cells in the small intestine or located at the very bottom
of the crypt in the colon. The intestinal stem cells, both +4 cells and CBC
stem cells give rise to the transitamplifying
population that undergoes vigorous division and differentiation into
enterocytes, goblet cells, and enteroendocrine cells as they migrate out of the
crypt onto the villi (3).
Fig. 1. Colonic crypt organization. a. In the epithelial lining of normal colonic mucosa, stem cells
(red) are located at the bottom of the crypts. Upon asymmetrical divisions, the
daughter cells undergoing differentiation migrate upward to give rise in turns
to transitamplifying (TA) precursors (light blue) and terminally differentiated
cells (pink). b. Cell types in the
colon epithelium. Intestinal stem cells generate three epithelial cell types:
the absorptive columnar cells, the hormone-producing enteroendocrine cells, and
the mucous-producing goblet cells.
Fig. 2. Models for
stem cells location of stem cells in intestinal crypts. a. The “+4
position” model suggests that intestinal stem cells are quiescent, slowly
cycling cells and located just above the
Paneth cells at position +4 relative to the crypt bottom (green). The
most important marker that identifies these cells is Bmi-1. b. The “stem
cell zone” model assumes active, rapidly cycling cells, so-called crypt base
columnar (CBC) cells (red), interspersed with Paneth cells, are
the true intestinal stem cells. The most important marker to identify these
cells is Lgr5.
The
Lgr5 gene encodes a leucine-rich repeat containing G-protein coupled
receptor, also known as Gpr49. Lgr5 expression is restricted to cycling CBC
cells and it has been demonstrated that Lgr5-expressing cells differentiate
into the expected functional lineages of the colonic epithelium (5).
Transcriptome analysis of Lgr5+ epithelial cells isolated from the bottom of
the small intestinal crypts led to the identification of a gene signature for
these Lgr5+ SCs. The OLFM-4 gene encodes a secreted molecule with unknown
function, originally cloned from human myeloblasts (6), which is enriched in
human colon crypts (7). Due to the very low expression levels of Lgr5, OLFM-4
has been recently proposed as a more faithful SC marker highly expressed in CBC
cells in human small intestine and colon (8).
Colorectal cancer stem cell identification
Tumors
are composed of a heterogeneous mixture of cancer cells at various levels of
differentiation, very similar to the structure of an organ. Recently, the
“cancer stem cell” model of tumorigenesis has proposed that within the tumor
mass there is a predetermined cell population with a ‘‘stem cell’’ phenotype,
able to perpetuate the cancer, while the rest of the tumor cells are incapable
of self-renewal (9). Even though it has long been assumed that mutations within
adult colonic stem cells may induce neoplastic transformation, the proof of
existence of colorectal cancer stem cells (CRC-SCs) has been hindered in the
past years by difficulties in identifying a specific biomarker for this rare
cell population. Only recently, new evidence has been provided that supports
the existence of CRC-SCs, confirming that the tumorigenic cell population of
CRC can be isolated on the basis of the expression of specific cell surface
biomarkers (9). The standard analysis to ascertain the existence of a
subpopulation of cancer stem cells (CSCs) is the demonstration that these cells
can transfer the tumor in immunocompromised mice and replicate the phenotypic
heterogeneity of the parental tumor. Several recent studies have evaluated the
functionality of specific CRC-SC biomarkers by using a combination of flow
cytometry to identify a “putative” SC population and xenograft models involving
immunodeficient mice to determine their tumor initiating potential (9).
In
the first two studies, CD133, also known as Prominin-1, was employed to
identify the tumorigenic cell population within CRC and metastatic (10, 11).
When transplanted into the renal capsule of NOD/SCID mice, CD133+ cells readily
developed tumors displaying morphologic features equivalent to those of the
parental cancer. Tumor phenotype was further maintained upon serial
transplantation (10). Similarly, in the second study, a population of CD133+
cells, accounting for approximately 2.5% of tumor cells, was isolated from
colon cancer specimens and perpetuated in vitro as floating colonies or “tumor
spheres” (11). CD133+ cells readily gave rise to tumors in mice,
whereas the CD133− cell population was unable to generate tumors
even after serial transplantation in mice (9). Both studies demonstrated the
expression of CD133 also in normal colon tissue, although at a lower frequency,
reinforcing the hypothesis that CD133+ CRC-initiating cells in cancer samples
might result from oncogenic transformation of normal colonic SCs.
Subsequently,
one study proposed CD44 and the epithelial surface antigen (EpCAM) as
CRC-SC-specific markers, with further enrichment by CD166. Purified CD44+/Ep- CAMHIGH
cells injected into NOD/SCID mice resulted in high frequency generation of
tumor xenograft. In contrast, CD44-/EpCAMLOW cells lack tumor
initiating activity (12). Further subfractionation of the CD44+/EpCAMHIGH
cell population by using the mesenchymal stem cell marker CD166 increased the
success of tumor xenograft.
Finally,
in a more recent study, aldehyde dehydrogenase 1 (ALDH) has been proposed as a
promising new marker for normal and malignant human colonic SCs (13). Flow
cytometric isolation of ALDH1+ cancer cells and implantation of as
few as 25 cells in NOD/SCID mice generate tumor xenografts. Further isolation
of cancer cells using a second marker (CD44 or CD133 serially) only modestly
increased enrichment based on tumor-initiating ability.
In
an another study, reported that in primary colon cancer samples from humans and
mice, CD133 was expressed in all epithelial, EpCAM+ cells in the malignant
tissue and that CD133 expression was excluded from the non-epithelial cell
components of the tumor (14). Thus, they proposed that the inability of CD133-
to generate tumors could be simply due to their non-epithelial nature.
Furthermore, the same authors demonstrated that both, CD133+/EpCAM+ and
CD133-/EpCAM+ cell populations, isolated from liver metastasis of colon cancer,
were able to generate tumors upon serial transplantation into NOD/SCID mice
(14).
A
comparison of expression of the three markers CD133, CD44 and CD166 that have
been associated with CRC-SCs revealed that the expression of CD133 correlates
with that of CD166, whereas both do not correlate with CD44, confirming that
CD133 is, alone, the best marker to predict poor patient survival (15).
Identification
of biomarkers for CRC-SCs will improve the understanding of the mechanism
underlying tumor growth and progression. Once again, studies performed on mouse
model could offer helpful suggestion. Recently, one study provided a very
convincing demonstration of the origin of intestinal cancer from Lgr5+
CBC cells. The authors have shown that deletion of APC in Lgr5+ expressing
cells leads to their transformation within days, suggesting that Lgr5 may mark
not only normal intestinal stem cells, but also a limited population of CSCs
(16). Simultaneously, using knock-in LacZ reporter mice within the
Prominin-1 (Prom1) locus, in a study have shown that Prom1+ cells,
located at the base of the crypts in the small intestine, co-express Lgr5,
generate the entire intestinal epithelium and are susceptible to neoplastic
transformation (17).
From
a clinical point of view, a recent study showed that Lgr5 was markedly
over-expressed in the majority of advanced CRCs compared with normal mucosal
tissue (18). As expected, in situ hybridization analysis confirmed the
expression of Lgr5 in CBC cells in both small intestine and colon. This Lgr5
expression, which was variable among CRC cases, correlated significantly with
lymphatic and vascular invasion, lymph node metastasis and tumor stage,
suggesting the involvement of this marker in tumor progression.
It
might be summarized the markers that have been used to isolate CRC-ICs, shown
in table 1 (9).
Table 1 Markers that have been proposed to characterize normal
intestinal SCs and used to isolate CRC-ICs
|
Marker
|
Function
|
|
|
Normal intestinal
stem cells
|
Musashi-1
|
RNA-binding
protein
|
|
Hes-1
|
Transcriptional
repressor
|
|
|
EphB
receptors
|
Cell
surface receptors
|
|
|
Bmi-1
|
Policomb-repressor
protein
|
|
|
Lgr5
|
Unknown,
WNT target gene
|
|
|
Aldh-1
|
Enzyme
|
|
|
Colon
cancer stem cells
|
CD133
|
Unknown
|
|
CD44
|
Hyaluronic
acid receptor
|
|
|
CD166
|
Adhesion
molecule
|
|
|
Aldh-1
|
Enzyme
|
Clinical
implications of colorectal cancer stem cells
The
CSC model has important implications for cancer therapy. At present, anticancer
therapies for CRC include surgery, radiation, chemotherapy, and anti-VEGF or
EGFR monoclonal antibodies. In most cases, many current cancer therapies target
the most rapidly dividing cells, which represent the majority of the tumor cell
population. Similarly, CRC-SCs have been found to be enriched in colon tumors
following classical chemotherapeutic regimens and remain capable of rapidly
regenerating tumor from which they were derived (19). The authors have further
demonstrated that resistance is mediated, at least in part, by ALDH1 enzyme
activity.
Together
with resistance to chemotherapy, CSCs are frequently resistant to standard
radiotherapy regimens. In this respect, it has been recently demonstrated that
resistance to radiation of CD133+ glioblastoma SCs can result from elevated
expression of DNA damage response genes (20). Radiotherapy for glioblastoma is
associated with an increase in the proportion of the CD133+ fraction.
In
another study, has recently demonstrated that the up-regulation of
interleukin-4 (IL-4) in CD133+ CRC-SCs is an important mechanism that protects
these tumorigenic cells from apoptosis. CD133+ CRC-SCs produce IL-4 as an
autocrine growth factor promoting tumor resistance to chemotherapeutic agents
such as 5-fluorouracil and oxaliplatin (21). This phenomenon was confirmed in xenografts
in which the administration of anti- IL-4 antibodies significantly reduced
tumor growth after chemotherapy.
In
a recent study, generated CD133+ tumor sphere cultures from several colon
cancer specimens and performed mass-spectrometry-based quantitative proteomics in
order to identify cell surface proteins enriched on culture tumor cells (22).
These cells retain the expression of cell surface markers such as CD133, CD166,
CD44 and EpCAM as well as other stem cell-associated proteins including nestin,
Bmi1 and Msi-1, thus confirming the value of this in vitro model for biological
analysis of CSC populations as well as for drug screening experiments.
Conclusion
Increasing
evidence shows that CRC-SCs may play a critical role in tumor development and progression.
CRC-SC resistance to conventional therapies may explain why it is difficult to
completely eradicate cancer and why recurrence is often inevitable. Thus, the
identification and molecular characterization of CSCs is critical to develop
therapeutic strategies that specifically target this rare population of cells
and that are likely to be effective in eradicating tumors and in reducing the
risk of relapse and metastasis.
References
1.
Jemal
A, Siegel R, Ward E, Murray T, Xu J,
Smigal C, Thun MJ. Cancer statistics. CA
Cancer J Clin. 2006 Mar-Apr;56(2):106-30.
2.
Boman
BM, Wicha MS. Cancer stem cells: a step
toward the cure. J Clin Oncol. 2008 Jun 10;26(17):2795-9.
3.
Radtke F,
Clevers H. Self-renewal and cancer of the gut: two sides of a coin. Science 2005;
307: 1904-09.
4.
Barker N,
van de Wetering M, Clevers H. The intestinal stem cell. Genes Dev 2008; 22:
1856-64.
5.
Barker N,
van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A,
Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in
small intestine and colon by marker gene Lgr5. Nature 2007; 449:
1003-07.
6.
Van der Flier LG,
van Gijn ME, Hatzis P, Kujala P, Haegebarth A, Stange DE, Begthel H, van den
Born M, Guryev V, Oving I, van Es JH, Barker N, Peters PJ, van de Wetering M,
Clevers H. Transcription factor achaete scute-like 2 controlsintestinal stem
cell fate. Cell 2009; 136: 903-12.
7.
Kosinski C,
Li VS, Chan AS, Zhang J, Ho C, Tsui WY, Chan TL, Mifflin RC, Powell DW, Yuen
ST, Leung SY, Chen X. Gene expression patterns of human colon tops and basal
crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl
Acad Sci USA 2007; 104: 15418-23.
8.
Van der Flier LG,
Haegebarth A, Stange DE, van de Wetering M, Clevers H. OLFM4 is a robust marker
for stem cells in human intestine and marks a subset of colorectal cancer
cells. Gastroenterology 2009; 137: 15-17.
9.
Ricci-Vitiani L,
Fabrizi E, Palio E, De Maria R. Colon cancer stem cells. J Mol Med 2009;
87: 1097-104.
10. O’Brien
CA, Pollett A, Gallinger S, Dick JE. A
human colon cancer cell capable of initiating tumour growth in immunodeficient
mice. Nature 2007; 445: 106-10.
11. Ricci-Vitiani
L, Lombardi DG, Pilozzi E, Biffoni M,
Todaro M, Peschle C, De Maria R. Identification and expansion of human
colon-cancer-initiating cells. Nature 2007; 445: 111-15.
12. Dalerba
P, Dylla SJ, Park IK, Liu R, Wang X, Cho
RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C,
Clarke MF. Phenotypic characterization of human colorectal cancer stem cells. Proc
Natl Acad Sci USA 2007; 104: 10158-163.
13. Huang
EH, Hynes MJ, Zhang T, Ginestier C, Dontu
G, Appelman H, Fields JZ, Wicha MS, Boman BM. Aldehyde de-hydrogenase 1 is a
marker for normal and malignant human colonic stem cells (SC) and tracks SC
overpopulation during colon tumorigenesis. Cancer Res 2009; 69:
3382-89.
14. Shmelkov
SV, Butler JM, Hooper AT, Hormigo A,
Kushner J, Milde T,et. al. CD133 expression is not restricted to stem cells,
and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J
Clin Invest 2008; 118: 2111-20.
15. Horst
D, Kriegl L, Engel J, Kirchner T, Jung A.
Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166
in colorectal cancer. Cancer Invest 2009; 27: 844-50.
16. Barker
N, Ridgway RA, van Es JH, van de Wetering
M, Begthel H, et.al. Crypt stem cells as the cells-of-origin of intestinal
cancer. Nature 2009; 457: 608-11.
17. Zhu
L, Gibson P, Currle DS, Tong Y,
Richardson RJ, Bayazitov IT, Poppleton H, Zakharenko S, Ellison DW, Gilbertson
RJ. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic
transformation. Nature 2009; 457: 603-07.
18. Uchida
H, Yamazaki K, Fukuma M, Yamada T,
Hayashida T, Hasegawa H, Kitajima M, Kitagawa Y, Sakamoto M. Overexpression of
leucine-rich repeat-containing G protein-coupled receptor 5 in colorectal
cancer. Cancer Sci 2010; Epub ahead of print.
19. Dylla SJ,
Beviglia L, Park IK, Chartier C, Raval J, Ngan L, et.al. Colorectal cancer stem
cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE 2008;
3:2428.
20. Bao
S, Wu Q, McLendon RE, Hao Y, Shi Q,
Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance
by preferential activation of the DNA damage response. Nature 2006; 444:
756-760.
21. Todaro
M, Alea MP, Di Stefano AB, Cammareri P,
Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, Stassi G.
Colon cancer stem cells dictate tumor growth and resist cell death by
production of interleukin-4. Cell Stem Cell 2007; 1: 389-402.
22. Fang
DD, Kim YJ, Lee CN, Aggarwal S, McKinnon
K, Mesmer D, Norton J, Birse CE, He T, Ruben SM, Moore PA. Expansion of
CD133(+) colon cancer cultures retaining stem cell properties to enable cancer
stem cell target discovery. Br J Cancer 2010; 102: 1265-1275.
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