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Old 11-24-2010, 09:41 AM
Dross Dross is offline
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Default Discovery halts breast cancer stem cells

Breast cancer stem cells (CSCs), the aggressive cells thought to be resistant to current anti-cancer therapies and which promote metastasis, are stimulated by estrogen via a pathway that mirrors normal stem cell development. Disrupting the pathway, researchers were able to halt the expansion of breast CSCs, a finding that suggests a new drug therapy target. The study, done in mice, is published in the Proceedings of the National Academy of Sciences (PNAS) Early Edition this week.

"A critical aspect of our work was to discover that estrogen could promote breast cancer growth by modulating the proportion of breast CSCs. Since CSCs were not directly sensitive to estrogen, it wasn't clear how estrogen could affect their numbers. However, we found that hormone-sensitive cancer cells can communicate with CSCs to regulate their numbers. By disrupting the interaction between cancer cell populations we were able to prevent tumor growth," said Charlotte Kuperwasser, PhD, associate professor in the anatomy and cellular biology and radiation oncology departments at Tufts University School of Medicine, and member of the genetics and cell, molecular & developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

"Interestingly, this signaling pathway involves many of the same players that control normal stem cell biology, raising a more general possibility that CSCs in other tumors might be regulated by the mechanisms guiding normal development," said Kuperwasser.

Kuperwasser and colleagues from MIT and Harvard used a mouse model to examine the behavior of cancerous human breast tissue with a method that mimics the human body more closely than standard mouse models. The researchers first examined estrogen's effect on breast CSC growth, finding that estrogen caused breast CSC numbers to increase by nearly 800 percent. Since few breast CSCs contain estrogen receptors, the researchers suspected that estrogen's actions were through a signaling mechanism from nearby cells that express the receptors.

"When nearby cells were exposed to estrogen, they secreted 14 times more FGF9, a signaling protein that drives CSC proliferation. When we blocked the FGF pathway with a small molecule inhibitor, we saw loss of CSC growth, tumorspheres generation, and even tumor formation. We then linked FGF signaling to the Tbx3 signaling axis, which is also important for embryonic mammary gland development," said first author Christine Fillmore, PhD, a 2009 graduate of the genetics program at the Sackler School and currently a research fellow in genetics at Children's Hospital Boston.

"These results show that interfering with this signaling pathway is a promising strategy for targeting breast CSCs. We are hopeful that the improved understanding of the mechanisms that promote breast CSCs will lead to the development of drugs that can be used to halt CSC proliferation," said Kuperwasser.

Kuperwasser also leads a laboratory at the Molecular Oncology Research Institute (MORI) at Tufts Medical Center, which is dedicated to the exploration of the molecular mechanisms of cancer and the translation of findings into the clinic.

Last edited by gdpawel : 02-25-2012 at 04:16 PM. Reason: post full article
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Old 01-25-2011, 12:46 PM
gdpawel gdpawel is offline
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Default Breast Cancer Stem Cells: A New Target for Therapy

Breast Cancer Stem Cells: A New Target for Therapy

By Giulia Federici, MS, Virginia Espina, MS, Lance Liotta, MD, PhD, Kirsten H. Edmiston, MD

January 22, 2011

Oncology. Vol. 25 No.1
ABSTRACT: Normal adult tissue stem cells awake from a dormant state to grow, differentiate, and regenerate damaged tissue. They also travel in the circulation and colonize distant organs at sites undergoing tissue repair. These same traits are utilized or co-opted by metastatic cancer cells. The cancer stem cell theory proposes that tumors emerge from a subpopulation of cancer cells that possess stem cell properties. This theory has profound implications for therapy. A small number of cancer stem cells may lie dormant following conventional therapy and tumor remission, only to re-emerge and regenerate the entire recurrent cancer. Consequently, it has been proposed that targeting cancer stem cells is the only way to obtain durable cancer treatment responses. Several strategies for targeting cancer stem cells have been proposed. Nevertheless, a number of issues must be investigated and resolved before effective treatments targeting cancer stem cells can enter clinical testing.

The cancer stem cell (CSC) theory was first proposed to explain the fact that only a small proportion of leukemia or solid tumor cells have the capacity to induce growing tumors in immunodeficient mice.[1,2] This tumorigenic subpopulation was found to possess stem cell markers, and to form spheroids in culture. In 1997, Bonnet and Dick isolated a subpopulation of myeloid leukemia cells that express a specific surface marker—CD34—but lack the CD38 marker. These cells were able to initiate leukemia in non-obese diabetic, severe combined immunodeficient (NOD/SCID) mice.[3] In 2003, Al-Hajj and his colleagues demonstrated that only a small subpopulation of CD44+/CD24low cells isolated from human breast cancer tissue were able to develop a tumor in immunodeficient mice.[4]

Following these initial reports, a number of labs have harvested and studied CSCs from virtually every major type of cancer. In vitro, CSCs grow as three-dimensional cellular aggregates, called spheroids, ranging up to 300 microns in diameter. Populations of CSC spheroids can be maintained in vitro after several passages of dissociation.[1] CSCs from different subtypes of cancer have different characteristic surface markers. Breast cancer stem cells are thought to be CD44high and CD24low.[4] In vitro and in animal models, CSCs have been found to be resistant to conventional chemotherapy and are thought to “lie in wait” in a dormant state within the tumor microenvironment, even when the major bulk of non-CSC tumor cells are killed by the therapy.[5]

It is possible to monitor CSC division by treatment with PKH26 fluorescent dye prior to transplantation. Studies using this dye have shown that self-renewal in CSCs is frequently driven by symmetric division instead of asymmetric divisions;[6,7] this division leads to the formation of two identical CSCs (or differentiated cells)—unlike division in normal stem cells, in which a single division always results in the formation of a stem cell and a committed cell. CSCs use this mechanism to enrich and regenerate the population within the bulk of the tumor. By dividing in this manner, it is hypothesized that CSCs persist over time to presumably regenerate the tumor in a manner analogous to the regeneration of damaged tissue by normal stem cells.[8,9]

The cellular pathways involved in the regulation of dormancy vs growth within the CSC tumor niche include the Notch,[10] Wnt,[11,12] and Hedgehog[13] pathways. These same pathways are also commonly used by normal stem cells, since they contribute in different ways to “stemness”—for example, by suppressing differentiation or by promoting an adherence-independent state.

Once CSCs have been triggered to emerge, they respond to external stimuli, proliferate, and recapitulate the original histomorphology of the tumor. CSCs, depending on the tissue of origin, express the same markers (eg, CD34 and CD133) and intracellular proteins (eg, ALDH, Nanog, Sox2, and Oct3/4) found in normal stem cells of the same tissue.[14,15] For this reason, many have postulated that CSCs are transformed normal stem cells. Normal stem cells exist in a wide spectrum of differentiated states, ranging from primitive pluripotent cells to partially committed progenitor cells to fully committed and differentiated cells. At any point in this range of commitment states, a neoplastic genetic lesion can occur during cell division. Such an occurrence induces a tumor with a phenotype that is frozen in the differentiated state of the original stem cell or progenitor cell that sustained the genetic carcinogenic hit.[16]

Although CSCs may be resistant to DNA-damaging chemotherapy when they are in a dormant, nonproliferative state, they may also be resistant to standard therapies intrinsically. Glioma CSCs have been shown to be radioresistant; they activate DNA checkpoints and thereby amplify the rate of DNA repair following radiation-induced damage. After radiation therapy, it has been found that glioblastomas are enriched in CD133+ CSCs. This is thought to be a consequence of a higher survival rate of the CSCs compared with that of the bulk of the glioblastoma.[17]

Normal stem cells travel in the circulation, extravasate, intravasate, invade, and colonize normal tissue during regeneration and healing. In addition, normal stem cells induce angiogenesis in healing tissues.[8,18,19] These same physiologic invasion programs are employed by CSCs. Thus, CSCs are thought to be enriched during invasion and metastasis. In fact, the level of stem cell markers in a tumor or a lymph node metastasis has been proposed to correlate with tumor aggressiveness.[20,21]

Tumors are known to be highly heterogeneous. CSCs may contribute to this histologic, cytologic, and morphologic heterogeneity. It has even been suggested that CSCs can contribute to the vascular and stromal elements in the tumor microenvironment.

The CSC theory remains controversial and may not explain many types of cancer; only some types of cancer may be driven by CSCs. Depending on the original cell or cells that are genetically altered during the carcinogenic process, a given tumor may, or may not, be sustained by CSCs.[8,22]
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Old 01-25-2011, 12:47 PM
gdpawel gdpawel is offline
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Default Breast Cancer and Breast Cancer Stem Cells

Breast cancer is the most common form of cancer diagnosed in women worldwide, affecting about 10% of women. Although the rate of mortality as a result of breast cancer has decreased in Western countries due to earlier detection, the incidence of breast cancer has risen by 30% in developed countries in the last decade.[23]

The first evidence of a CSC origin for solid tumors was demonstrated by Al-Hajj et al in 2003 in breast tumors. They isolated a small subpopulation of cells that were CD44+ (alone or in conjunction with ESA [epithelial specific antigen]) and CD24-, and that were able to generate a tumor in NOD/SCID mice. Breast CSCs are propagated in vitro through the formation of anchorage-independent “mammospheres,” a term for mammary cell spheroids. Mammospheres are not composed homogeneously of CD44+/CD24- cells; after dissociation of the spheres and fluorescent-activated cell sorting (FACS) analysis, only a subpopulation of the cells are found to be CD44+/CD24-. Nevertheless, this subpopulation of cells are still able to generate mammospheres in in vitro conditions and to produce tumors in suitable immunodeficient mice.[4]

Breast CSCs (BCSCs) have been examined by many investigators hoping to find a specific marker that can be used for routine identification or to serve as a therapeutic target. Elevated levels of ALDH1 expression give CD44+/CD24- cells higher tumorigenic activity after in vivo assays. Moreover, BCSCs show an enhanced PKH26 dye-retaining capacity, providing an indirect measure of dormancy. PKH26 dye binds irreversibly to cell membranes and it is divided among daughter cells only when a cell undergoes division. The less the cells divide, the less dye is lost. A higher dye content may be a means of identifying quiescent BCSCs.[6]

BCSCs can originate from normal breast stem cells within the gland that gives rise to epithelial or myoepithelial cells that line the duct or generate the alveoli.[24] At any stage of cellular differentiation or commitment, a breast stem cell can be subject to a carcinogenic insult. A tumor that forms at this point will retain the differentiated program of the original stem or progenitor cell, and the breast cancer that is established will exhibit a differentiated pattern and a morphology that heralds back to the state of differentiation of the originating breast stem cell or progenitor cell at the time of carcinogenesis.

Breast cancer progenitor cells with stem-like properties, an invasive phenotype, and the propensity to form spheroids have recently been isolated for the first time from human breast premalignant lesions.[19] This finding indicates that the malignant phenotype of breast cancer may be determined very early in the course of the disease and may exist in a dormant state in premalignant lesions, such as ductal carcinoma in situ.

The World Health Organization has classified 30 morphologic types of breast cancer on the basis of histology and molecular alterations. Major categories of breast cancers often used, based on defining molecular subtypes, are luminal type A, luminal type B, the basal type, and the ErbB2-positive type.[25,26] The luminal-type breast cancers are thought to derive from differentiated luminal cells; these are estrogen receptor (ER)-positive and HER2-negative. The basal-type tumors are double negative—that is, negative for both ER and HER2. This type of tumor is thought to derive from luminal progenitor cells, and it is the subtype most commonly associated with BRCA1 mutations. ErbB2-type tumors may be derived from late luminal progenitors that have undergone HER2 gene amplification.

If BCSCs are the cause of breast cancer treatment failure, then why haven’t investigators used BCSC markers to target therapies directly to the BCSCs? The first reason is that stem cell markers found on CSCs are also present in normal tissue stem cells. Thus, it is possible that a therapy that killed cells bearing a stem cell marker would kill normal stem cells as well as CSCs. In addition, markers thought to be expressed on BCSCs may not be specific. The exclusive use of CD44 and CD24 to identify and isolate BCSCs is a controversial topic.[27] The frequency of CD44+/CD24- cells within breast tumors varies significantly depending on the tumor subtype and the histologic stage. CD44+/CD24- cells are generally enriched in basal-type breast cancers as well as in cells that have undergone epithelial-to-mesenchymal transition.[28] In contrast, only about 1% of luminal-type cell populations consist of CD44+/CD24- cells. Moreover, not all CD44+/CD24- cells have the same grade of tumorigenicity if injected into xenografts.[21] Thus, CD44+/CD24- marker levels are not specific for actual tumor-forming cells. Some have suggested that the presence of CD44+/CD24- cells could be more related to the cancer subtype (eg, basal-like), rather than an actual reflection of stem cells within the tumor bulk.[27,29] Since CD44+/CD24- characterization is not sufficient for isolation of the entire BCSC pool, there is a great need for a deeper characterization of the BCSC compartment in order to target these cells for therapy.
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Old 01-25-2011, 12:49 PM
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Treatment Strategies

Theoretically, we could target CSCs through a combination of strategies that would be specific for the amplified or altered genome of CSCs and spare normal adult stem cells. HER2-amplified, ErbB2+ tumors are currently treated with inhibitors of the epidermal growth factor (EGF) receptor family, including trastuzumab (Herceptin) and lapatinib (Tykerb). However, this treatment would be effective against CSCs only if the HER2 gene were amplified at the level of the stem cell. If a cell with ErbB2 amplification were to emerge after several divisions from a CSC in which there was no original amplification, the cancer stem compartment would not be affected by EGF receptor family drugs. Moreover, CSCs, regardless of HER2 amplification status, may be driven by signaling pathways that are different from those that drive their differentiated progeny. This is why, although drugs that inhibit the EGF receptor family are initially efficacious, there is often the relapse of the tumor.[6]

A second approach is to force the CSCs into a differentiated state, thereby impairing stem characteristics, such as self-renewal. Administration of retinoic acid,[24] or interference with the Notch, Wnt, or Hedgehog pathways that are thought to regulate differentiation,[12] are strategies that have been proposed.

Another approach is to destabilize the stem cell niche, which is thought to protect the CSCs in a sequestered, non-dividing dormant state. Disregulating the supporting cells in the stem cell niche could theoretically deplete the dormant CSCs.[19] If CSCs are resistant to therapy because they are enriched in drug efflux pumps, then targeting the membrane transporters, such as adenosine triphosphate–binding cassette (ABC) pumps, could potentially sensitize the CSCs to chemotherapy.[1] It has been proposed that reversing the active state of stem cell–related genes, such as Oct 3/4, Sox2, and Nanog, through the use of epigenetic manipulation could knock out the CSC phenotype.[30] CSCs are apoptosis-resistant, it is thought, in order to secure the production of progeny. This resistance could be caused by intracellular mechanisms that lead to a blockade in the apoptotic pathways— for example, an overexpression of anti-apoptotic molecules (Bcl-2, Bcl-XL) or a downregulation of Caspases. These negative regulators of apoptosis are candidate therapeutic targets.[19]

Conclusions

Although the concept of CSCs remains controversial, most investigators acknowledge the presence of a subpopulation of tumor-initiating cells within the tumor bulk. These cells have stem cell characteristics, including self-renewal, pluripotency, and motility. This phenotype is the basis for the name “cancer stem cells.” In breast tumors, as well as in other tumors, CSCs or progenitor cells may constitute a subpopulation that remains following a treatment-induced regression of the bulk of the tumor mass. According to the CSC hypothesis, tumor recurrence results from expansion of the CSC subpopulation in a way that reconstitutes the tumor mass. The CSC hypothesis can explain the prevalence of cancer treatment failure, but presently there are no clinical treatment strategies that directly target CSCs. There is an urgent need to investigate critical biologic questions that may yield strategies for successful and specific targeting of CSCs. These questions include a) when and how CSCs or progenitor cells first originate, b) how CSCs differ from normal adult stem cells, c) which regulatory events are responsible for dormancy or for the emergence of CSCs within a tissue niche, d) how the individual characteristics of tumor-specific CSCs may differ from one patient to the next, and e) how the original genomic characteristics of a cancer stem clone dictate the histology and clinical behavior of the tumor that emerges.
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Old 01-25-2011, 12:50 PM
gdpawel gdpawel is offline
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Default References

1. Dontu G, Abdallah WM, Foley JM, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003;17:1253-70.

2. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367:645-8.

3. Bhatia M, Wang JC, Kapp U, et al. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A. 1997; 94:5320-5.

4. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983-8.

5. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275-84.

6. Cicalese A, Bonizzi G, Pasi CE, et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2009;138:1083-95.

7. Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006;441:1068-74.

8. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105-11.

9. Vermeulen L, Sprick MR, Kemper K, et al. Cancer stem cells—old concepts, new insights. Cell Death Differ. 2008;15:947-58.

10. Farnie G, Clarke RB. Mammary stem cells and breast cancer--role of Notch signalling. Stem Cell Rev. 2007;3:169-75.

11. Liu S, Dontu G, Wicha MS. Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res. 2005;7:86-95.

12. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843-50.

13. Zardawi SJ, O’Toole SA, Sutherland RL, Musgrove EA. Dysregulation of Hedgehog, Wnt and Notch signalling pathways in breast cancer. Histol Histopathol. 2009;24:385-98.

14. Bussolati B, Bruno S, Grange C, et al. Identification of a tumor-initiating stem cell population in human renal carcinomas. Faseb. J 2008;22:3696-705.

15. Tomuleasa C, Soritau O, Rus-Ciuca D, et al. Isolation and characterization of hepatic cancer cells with stem-like properties from hepatocellular carcinoma. J Gastrointestin Liver Dis. 2010;19:61-7.

16. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene. 2004;23:7274-82.

17. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756-60.

18. Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters. Cancer Res. 2006;66:4553-7.

19. Sneddon JB, Werb Z. Location, location, location: the cancer stem cell niche. Cell Stem Cell. 2007;1:607-11.

20. Brabletz T, Jung A, Spaderna S, et al. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5:744-9.

21. Sheridan C, Kishimoto H, Fuchs RK, et al. CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 2006;8:R59.

22. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755-68.

23. American Cancer Society. Cancer facts and figures 2010. Atlanta: American Cancer Society; 2010.

24. Gudjonsson T, Ronnov-Jessen L, Villadsen R, et al. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. J Cell Sci. 2002;115(Pt 1):39-50.

25. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-52.

26. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869-74.

27. Lawson JC, Blatch GL, Edkins AL. Cancer stem cells in breast cancer and metastasis. Breast Cancer Res Treat. 2009;118:241-54.

28. Giatromanolaki A, Sivridis E, Fiska A, Koukourakis MI. The CD44+/CD24- phenotype relates to ‘triple-negative’ state and unfavorable prognosis in breast cancer patients. Med Oncol. 2010; [Epub ahead of print]

29. Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11:259-73.

30. Ting AH, McGarvey KM, Baylin SB. The cancer epigenome—components and functional correlates. Genes Dev. 2006;20:3215-31.
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Old 01-03-2013, 11:55 AM
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Default How A Common Breast Cancer Evades Treatment

A new study reveals a surprising paradox about stem cells in breast cancer: one whose discovery may explain how a common breast cancer evades treatment, and improve diagnosis and treatment of the disease.

US researchers studying breast tumors thought to be HER2-negative, found they contained small groups of aggressive, treatment-resistant HER2-positive breast cancer stem cells (BCSCs).

Jian Jian Li, director of translational research in the Department of Radiation Oncology at the University of California Davis School of Medicine in Sacramento, and colleagues, describe how they uncovered these paradoxical characteristics in the 15 December issue of the journal Clinical Cancer Research.

HER2

HER2 is a receptor that is present on the surface of certain cancer cells. Receptors are special proteins that allow ligands, other proteins or compounds, to attach to them (like a lock accepting a unique key). Such attachments trigger particular cell processes, such as growth and repair.

When human epidermal growth factor attaches itself to HER2 receptors on breast cancer cells, it can trigger cell growth and proliferation.

A tumor is said to be HER2-positive when its cancer cells have a lot more HER2 receptors than other cancer cells. Estimates suggest 1 in 5 breast cancers have HER2-positive tumors.

HER2-positive tumors tend to be more aggressive and grow more quickly than other types of breast cancer.

HER2 status is one of the factors that clinicians test for in determining the type of breast cancer. They also test for two other receptors: estrogen receptor (ER) and progesterone receptor (PR).

Whether a tumor has HER2, ER, or PR, or all three, or none, can make a huge difference to its aggressiveness, the patient's overall prognosis and treatment options.

HER2-positive breast cancers are treated with drugs that target the protein, such as Herceptin or Tykerb, with good results.

However, until recently, clinicians would never have considered whether such drugs should also be given to patients with HER2-negative breast cancers.
HER2-Positive BCSCs Isolated from Irradiated, HER2-Negative Tumors

Li and colleagues isolated the HER2-positive BCSCs from irradiated, HER2-negative breast tumors.

They also checked the stem cells for CD44 and CD24, cell surface proteins that act as BCSC markers and indicate how aggressive the cancer is.

They found BCSCs that were HER2-positive, CD44-positive, and CD24-negative or -low, were more aggressive and highly resistant to radiotherapy.

But Herceptin and an emerging "gene silencing" treatment called short interfering RNA, appeared significantly to reduce these features.

57.1% of primary tumors and 84.6% of recurrent tumors contained HER2-positive and CD44-positive BCSCs, they found.

"These BSCSs are very resistant to traditional treatments, which can lead patients to relapse," says Li in a statement.

"Despite chemotherapy, radiotherapy or even surgery, the cancer is still recurrent. These findings change our concept of breast cancer because now we know HER2-negative breast cancers can be treated effectively with anti-HER2 treatments," he adds.

How the BCSCs Maintain Resistance to Treatment

The study also provides new insights into how the BCSCs maintain resistance to cancer treatment.

The researchers found evidence that a complex network of proteins, including HER2 and STAT3 (a transcription activator that controls gene expression), help regulate metastasis or cancer spread, cell death, and other cell processes. The network is what helps the cancer cells survive a whole range of traditional anti-cancer therapies.

The team believes their findings make a significant contribution, both to researchers and clinicians.

"We now have a better understanding of how BCSCs resist radiation and other treatments," explains Li.

Recent studies have shown that patients with HER2-negative breast cancer can benefit from HER2 treatments, but nobody could explain why.

This study provides a detailed reason for why HER2 treatment can benefit patients with HER2-negative breast cancers.

Opens New Diagnostic and Treatment Pathways

The researchers suggest their findings do more than propose a new treatment route: they also open a new diagnostic pathway for HER2-negative breast cancers.

Markers like CD44 could be used to identify aggressive,HER2-positive BCSCs in cancers that present as HER2-negative. This would allow treatment to be tailored to individual patients.

The study also opens a new treatment route for other cancers, as Li explains:

"This may open the possibility of treating HER2-positive stem cells in bone, lung or brain cancers, which are all difficult to treat in the later stages."

Funds from the National Institutes of Health and a grant from the US Department of Energy Office of Science helped finance the study.

Reference: "HER2-Associated Radioresistance of Breast Cancer Stem Cells Isolated from HER2-Negative Breast Cancer Cells"; Nadire Duru, Ming Fan, Demet Candas, Cheikh Menaa, Hsin-Chen Liu, Danupon Nantajit, Yunfei Wen, Kai Xiao, Angela Eldridge, Brett A. Chromy, Shiyong Li, Douglas R. Spitz, Kit S. Lam, Max S. Wicha, and Jian Jian Li; Clin Cancer Res 15 December 2012 18:6634-6647; DOI:10.1158/1078-0432.CCR-12-1436

Citation: "Surprising Discovery About Stem Cells Reveals How A Common Breast Cancer Evades Treatment." Medical News Today. MediLexicon, Intl., 17 Dec. 2012.

[url]http://clincancerres.aacrjournals.org/content/18/24/6634.abstract
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Old 01-03-2013, 12:46 PM
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Default HER2 Therapy Could Be Useful in More Than 20% of Breast Cancers

Therapies targeted at HER2, such as trastuzumab (Herceptin), have revolutionized the treatment of HER2-positive breast cancer in recent years, but this accounts for only 20% of all breast cancers.

However, new research suggests that these drugs may play a role in other breast cancers, because HER2 has been found in cancer stem cells (CSCs), the clump of "mother" cells that drives the disease. Although this small nest of cells accounts for only 1% to 5% of all breast cancer tissue, it is a crucially important driver that fuels its growth and spread.

Even if a breast tumor tissue sample tests negative for HER2, indicating that a patient is not a candidate for HER2-targeted therapies, the drugs could be useful because they would target the HER2 found in the little clump of CSCs.

This theory is supported by experimental data published online today in Cancer Research.

"If this is confirmed in clinical trials, it could alter our approach to breast cancer treatment," said senior author Max Wicha, MD, distinguished professor of oncology and director of the University of Michigan Comprehensive Cancer Center in Ann Arbor.


The idea of using drugs that cause tumors to shrink...is flawed.

The implication of this finding is that a 2-pronged approach to treatment is needed, the researchers suggest. One treatment approach would target the small cluster of CSCs, perhaps with HER2 therapy; the other, likely traditional therapy, would target the bulk tumor cells.

"This work has very significant implications," Dr. Wicha said in a statement. "The idea of using drugs that cause tumors to shrink, which has been the accepted paradigm for developing therapies, is flawed."

"Our work suggests that adjuvant therapies will need to target the cancer stem cell population," he explained. Eliminating the CSCs should prevent tumor recurrence and ultimately result in more cures.

Molecular Explanation for Clinical Findings

In their study, Dr. Wicha and colleagues report findings from laboratory research on breast cancer cell lines, human breast cancer tissue samples, and animal studies using xenograft models. Their results show that HER2 is selectively expressed in the CSC population of luminal estrogen-receptor-positive breast cancers that are negative for HER2 (i.e., show no HER2 gene amplification).

"These observations extend previous studies linking HER2 expression and CSC phenotypes in cell lines," the researchers write.

The findings also "provide a molecular explanation for the surprising finding" that some patients with breast cancer who tested negative for HER2 nevertheless benefited from adjuvant therapy with the targeted drug trastuzumab, Dr. Wicha noted.

He was referring to a "provocative" report that challenges the conventional wisdom that only patients with HER2-amplified breast tumors benefit from trastuzumab (N Engl J Med.2008;358:1409-1411).

That report details a pivotal trial showing the effectiveness of trastuzumab, and notes that 174 cases originally classified as HER2-postitive actually lacked HER2 gene amplification when they were reanalyzed in a central laboratory. Surprisingly, Dr. Wicha explained that the patients who turned out to be HER2-negative benefited from adjuvant trastuzumab to an extent similar to that seen in patients who displayed classic HER2 amplification.

Although there were questions about the reliability of the HER2 analyses in that study, similar results were reported by another group (J Clin Oncol. 2010; 28:4307-4315), which "makes it less likely that these results are due to chance or laboratory error," the researchers write.

"These studies have important implications for the development of clinical trials using HER-targeting agents by suggesting that a much larger group of women with breast cancer may benefit from HER2 blockade in the adjuvant setting than currently receive these treatments," Dr. Wicha and colleagues conclude.

The good news is that there are a number of HER2-targeted therapies already available. Trastuzumab, first approved in 1998, has since been joined by lapatinib (Tykerb), pertuzumab (Perjeta), and T-DM1 (Kadcyla), which was approved just last week.

Dr. Wicha reports receiving a commercial research grant from Dompe, having an ownership interest (including patents) in Oncomed Pharmaceuticals, and serving on the consultant/advisory board of Verastem and Paganini. Coauthor Hasan Korkaya, PhD, from the University of Michigan, reports receiving a commercial research grant from MedImmune.

Cancer Res. Published online February 26, 2013

Citation: HER2 Therapy Could Be Useful in More Than 20% of Breast Cancers. Medscape. Feb 26, 2013

[url]http://cancerres.aacrjournals.org/content/early/2013/02/14/0008-5472.CAN-12-3349.abstract
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Old 01-03-2013, 12:47 PM
gdpawel gdpawel is offline
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Default BRCA1 mutation linked to breast cancer stem cells

A study may explain why women with a mutation in the BRCA1 gene face up to an 85 percent lifetime risk of breast cancer.

Researchers from the University of Michigan Comprehensive Cancer Center found that BRCA1 plays a role in regulating breast stem cells, the small number of cells that might develop into cancers.

The study, in mice and in human breast cancer cells, found that BRCA1 is involved in the stem cells differentiating into other breast tissue cells. When BRCA1 is missing, the stem cells accumulate unregulated and develop into cancer.

Our data suggest that an important reason women with BRCA1 mutations get breast cancer is that BRCA1 is directly involved in the regulation of normal breast stem cells. In these women, loss of BRCA1 function results in the proliferation of breast stem cells. Since we believe that breast cancer may originate in these cells, this explains why these women have such a high incidence of breast cancer,ť said senior study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.

The study, published online in the Proceedings of the National Academy of Sciences, provides strong support for the hypothesis that a small number of cells, called cancer stem cells, are responsible for fueling a tumor's growth. Wicha's lab was part of the team that first identified stem cells in human breast cancer in 2003.

BRCA1 is one of two genes, that when mutated confers a high risk of breast and ovarian cancer. Previous research has shown that BRCA1 is involved in DNA repair, but it has been unclear why women with this gene mutation have such a high risk of breast cancer, up to 85 percent lifetime risk compared to 16 percent in the general population.

The cancers which develop in these women are generally a more aggressive form called triple negative type, because they do not express hormones or proteins, including estrogen, that can be targeted with therapies. In the current study using both mice and human breast cells, researchers found that BRCA1 regulated the development of the estrogen-receptor-negative stem cells into estrogen-receptor-positive cells. When BRCA1 is missing, genetically unstable stem cells accumulate and then may develop into breast cancers.

Researchers detected clusters of expanded stem cells in breast tissue isolated from women carrying BRCA1 mutations, and found that women with these expanded stem cells had a particularly high chance of developing breast cancer.

If larger studies confirm these findings, it could potentially lead to a test to identify BRCA1 carriers at particularly high risk of developing breast cancer. This might help them and their physicians make a more informed decision about preventative measures such as prophylactic mastectomy, Wicha says.

BRCA1 mutations are the most common cause of hereditary breast cancer, which account for approximately 10 percent of the 180,000 breast cancers diagnosed in the United States this year. For information about breast cancer, call the U-M Cancer AnswerLine at 800-865-1125. To learn more about cancer stem cells, visit [url]www.mcancer.org

In addition to Wicha, study authors were U-M research investigator Suling Liu; U-M research fellow Christophe Ginestier; Emmanuelle Charafe-Jauffret, M.D., Ph.D., from the Centre de Recherche en Cancerologie de Marseille in France; U-M research assistant Hailey Foco; Celina Kleer, M.D., Harold A. Oberman Collegiate Professor of Pathology and associate professor of pathology at U-M; Sofia Merajver, M.D., Ph.D., professor of internal medicine at U-M; and Gabriel Dontu, M.D., Ph.D., research assistant professor of internal medicine at U-M.

Funding for the study was from the National Institutes of Health. The University of Michigan has filed for patents covering these and related technologies, and, through its Office of Technology Transfer, is currently looking for commercialization partners to help bring the technology to market. Much of the work is being commercialized through OncoMed, a University of Michigan startup company in which Max Wicha and other U-M inventors hold a financial interest.
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  #9  
Old 02-27-2013, 02:01 AM
gdpawel gdpawel is offline
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Default Herceptin Targets Breast Cancer Stem Cells

A gene that is overexpressed in 20 percent of breast cancers increases the number of cancer stem cells, the cells that fuel a tumor's growth and spread, according to a new study from the University of Michigan Comprehensive Cancer Center.

The gene, HER2, causes cancer stem cells to multiply and spread, explaining why HER2 has been linked to a more aggressive type of breast cancer and to metastatic disease, in which the cancer has spread beyond the breast, the researchers say.

Further, the drug Herceptin, which is used to treat HER2-positive breast cancer, was found to target and destroy the cancer stem cells. Results of the study appear online in the journal Oncogene.

"This work suggests that the reason drugs that target HER2, such as Herceptin and Lapatanib, are so effective in breast cancer is that they target the cancer stem cell population. This finding provides further evidence for the cancer stem cell hypothesis," says study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.

The cancer stem cell hypothesis says that tumors originate in a small number of cells, called cancer stem cells, and that these cells are responsible for fueling a tumor's growth. These cells represent fewer than 5 percent of the cells in a tumor. Wicha's lab was part of the team that first identified stem cells in human breast cancer in 2003.

In the current study, researchers found that breast cancer cells overexpressing the HER2 gene had four to five times more cancer stem cells, compared to HER2-negative cancers. In addition, the HER2-positive cells caused the cancer stem cells to invade surrounding tissue, suggesting that HER2 is driving the invasiveness and spread of cancer.

The researchers then looked at the drug Herceptin, which is used to treat HER2-positive breast cancer. They found Herceptin reduced the number of cancer stem cells in the HER2-positive breast cancer cell lines by 80 percent, dropping it to the same levels seen in HER2-negative cell lines.

When HER2 was not overexpressed in the cell cultures, the researchers found, the cancer stem cell population did not increase. Nor did Herceptin have any effect on the HER2-negative cells, which is consistent with how Herceptin is used in the clinic.

"We are now studying what pathways are activated by HER2 overexpression. Our hope is that we could develop inhibitors of these pathways that might be effective in targeting cancer stem cells in women whose tumors do not overexpress HER2 or those who are resistant to Herceptin," says study author Hasan Korkaya, Ph.D., a U-M research fellow in internal medicine.

Breast cancer statistics: 184,450 Americans will be diagnosed with breast cancer this year and 40,930 will die from the disease, according to the American Cancer Society. About 20 percent of breast cancers are considered HER2-positive.

Reference: Oncogene, advance online publication June 30, 2008; doi: 10.1038/onc.2008.207

Source: University of Michigan Health System
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Old 02-27-2013, 02:03 AM
gdpawel gdpawel is offline
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Default Herceptin Targets Breast Cancer Stem Cells

Some patients' tumors respond to chemotherapy and some do not. A pathway/mechanism - cancer stem cells - may be the cause. To prevent cancer's return may require one therapy to shrink a tumor and another therapy to kill the abnormal seeds that sprouted it. Conventional cancer therapies have been good at shrinking tumors, but the ability to shrink tumors has little or no correlation to survival times. Newer treatments need to decrease the number of cancer stem cells.

There is a communication between stem cells and a tumor. It sends out a signal that make the different cells of the tumor and the cancer cells then (send chemical messages) that cycle back to the cancer stem cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in a cell.

Finding the protein that prevents cancer from metastasizing, isolating factors within the stem cell microenvironment, can influence tumor cell fate and reverse the cancerous properties of metastatic tumor cells. However, it is not the only tumor suppressive factor within the stem cell microenvironment. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

In some cases, targeted drugs may kill tumor cells without killing microvascular cells in the same time frame. In other cases, they may kill microvascular cells without killing tumor cells. Yet in other cases, they could kill both types of cells or neither type of cells. The ability to these targeted agents to kill tumor and/or microvascular cells in the same tumor is highly variable among the different agents.

You still need to measure the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific cancer drugs, not just the individual molecular targets. Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease.

Sources:
Cell Function Analysis
European Science Foundation
American Association for Cancer Research
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