Thread: Cancer stem cells: The root of all evil?
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Old 06-13-2009, 05:10 PM   #19
Rich66
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Interview with Max Wicha which includes reference to Repertaxin as well as discussion of Her2 connection to cancer stem cells.

Breast Cancer Stem Cells as Novel Therapeutic Targets: An Expert Interview With Dr. Max S. Wicha CME

Published: 01/20/2009


Editor's Note:
Increasing evidence suggests that breast cancers might be targets of transformation during carcinogenesis and that deregulation of self-renewal carried out by stem cells might be one of the key events involved in breast carcinogenesis. The understanding of the molecular pathways underlying these changes is increasing; these alterations are now known to involve pathways such as Hedgehog and Notch, which may represent novel targets of breast cancer development and recurrence. Studies are also identifying markers of stem cells, which may help further characterize the basal, luminal, and other subtypes of breast cancer. At the 31st Annual San Antonio Breast Cancer Symposium (SABCS), several presentations focused on breast cancer stem cells. Research in this area is just beginning and ultimately may help inform clinical practice and enable the development of novel treatment approaches. Medscape Oncology recently spoke about these advances with Max S. Wicha, MD, Distinguished Professor of Oncology at the University of Michigan, Ann Arbor. Dr. Wicha is principal investigator for some of the seminal studies in this area.
Medscape: What is the current thinking on the role of stem cells in the pathology and treatment of breast cancer?
Dr. Wicha: We have been interested in the concept that cancers are driven by a small component of cells that have stem cell properties and that targeting these cells may result in improved outcomes for patients with cancer. Our laboratory was the first to identify a small population of cells with stem cell properties in human breast cancers, and we found that these cells could be prospectively identified with use of cell surface markers.[1] Properties of these stem cells include the ability to be serially transplanted into immunosuppressed mice, as well as the ability to reproduce the heterogeneity of cells found in the initial tumor.
Research involving cell cultures and animal models has demonstrated that cancer stem cells are relatively resistant to chemotherapy and radiation therapy.[2,3] Recent clinical studies have supported this concept, including one study of neoadjuvant chemotherapy that demonstrated that the proportion of cells with stem cell markers increases after neoadjuvant chemotherapy.[4] In this neoadjuvant therapy study, women whose tumors overexpressed HER-2 had a higher number of stem cells than those with tumors that did not overexpress this gene. Furthermore, in contrast with chemotherapy, addition of the HER-2 inhibitor lapatinib recently has been found to reduce the proportion of breast cancer stem cells present following neoadjuvant therapy.[5] These results may be explained by our laboratory's recent findings that HER-2 is an important regulator of breast cancer stem cells and that HER-2 inhibitors such as trastuzumab or lapatinib are able to selectively target cancer stem cells.[6]
One of the biggest challenges we now face in breast cancer treatment is to develop more effective therapies that are able to target the breast cancer stem cell population. At the 2008 SABCS, I presented data showing that breast cancer stem cells are regulated by the tumor microenvironment.[7] Specifically, our group demonstrated that mesenchymal stem cells, which we believe originate in the bone marrow and "traffic" into tumors, are able to regulate breast cancer stem cells. The feedback loops between mesenchymal stem cells and breast cancer stem cells provide new targets for therapies aimed at eliminating the cancer stem cell population. We also found that when breast cancers are treated with chemotherapy, the dying cancer cells secrete the chemokine interleukin (IL)-8. This occurs as part of a normal damage response. However, IL-8 is able to stimulate cancer stem cells through the CXCR1 chemokine receptor. The interaction between dying cancer cells producing IL-8 and CXCR1 stimulation of cancer stem cells contributes to the increase in cancer stem cells following chemotherapy. In mouse models we have shown that we can block these pathways with use of an antibody or a small molecule inhibitor to the CXCR1 receptor and can thus directly target and reduce the cancer stem cell population.
Medscape: Would blocking the CXCR1 receptor be expected to reduce recurrence?
Dr. Wicha: Yes, that is our hypothesis -- that targeting cancer stem cells through the CXCR1 receptor would reduce recurrence, which may be driven by chemotherapy-resistant cancer stem cells. This is consistent with our findings in mouse models.
Medscape: What agents did you use against IL-8 or CXCR1 in your studies?
Dr. Wicha: We used antibodies against IL-8 or a small molecule inhibitor of CXCR1 called repertaxin. Repertaxin was developed as an anti-inflammatory agent to be used to prevent heart damage after myocardial infarction. Repertaxin has been tested in phase 1 clinical trials. Our studies indicate that this approach may provide a strategy to selectively target breast cancer stem cells.
Medscape: What other pathways might be involved in mediating stem cell signaling?
Dr. Wicha: It is becoming clear that a number of other signaling pathways regulate cancer stem cells. One important pathway is the Notch pathway. Small molecules, such as gamma secretase inhibitors, are able to inhibit Notch signaling; in mouse models, this Notch inhibitor has been shown to reduce the population of cancer stem cells. On the basis of this concept, phase 1 clinical trials that utilize gamma secretase inhibitors are now in progress at our cancer center as well as others. We are also trying to combine Notch inhibitors with cytotoxic chemotherapy such as docetaxel, inasmuch as our preclinical findings suggest that these signaling agents may sensitize cancer stem cells to chemotherapy.
The Hedgehog pathway may also regulate stem cells. The ligands for Hedgehog may act on cells in the tumor stroma, and the interaction between the stroma and breast cancer stem cells may regulate their growth. Small molecule Hedgehog inhibitors have now been tested in phase 1 clinical trials and are about to enter phase 2 trials for breast cancer. In light of recent studies[8,9] that have confirmed an important role for cytokine signaling in the regulation of breast cancer stem cells, future approaches may combine agents that can inhibit stromal cell signaling with stem cell inhibitors such as Notch and Hedgehog.
Recent studies suggest that characteristics of molecular subcategories of breast cancer may be driven by stem cells that can be identified with different markers.[10,11] These differences may result from the origin of breast cancers -- whether stem or progenitor cells -- or different mutations that drive the various molecular subtypes. Ultimately, molecular analysis of breast cancer self-renewal pathways may allow for the individualization of therapy designed to target these different stem cell populations.
Medscape: What were some other important findings related to breast cancer stem cells presented at SABCS this year?
Dr. Wicha: A study by Atkas and colleagues demonstrated that cancer cells that express stem cell markers could be isolated from circulating blood in 28 patients with metastatic breast cancer.[12] Furthermore, they showed that these cells expressed not only the stem cell marker aldehyde dehydrogenase (ALDH)-1 but also markers of epithelial-mesenchymal transition (EMT), a phenotypic change that may allow cells to travel to the site of metastasis formation while avoiding elimination by standard treatment. Markers of EMT that have been investigated include Twist, Akt2, and PI3K. Samples were also investigated separately for the stem cell marker ALDH-1. Circulating tumor cells (CTCs) were detected in 12 of 28 (43%) breast cancer samples. In the samples that were positive for CTCs, 50% were positive for at least one EMT marker and 42% were positive for ALDH-1. In the group that was negative for CTCs, only 19% and 12% expressed EMT markers or ALDH-1, respectively. These studies suggest that cancer stem cells can display an EMT phenotype and that these cells are relatively resistant to chemotherapy and can be detected in the circulation.
Medscape: What are some of the important stem cell markers currently under investigation?
Dr. Wicha: Our laboratory was the first to show that expression of the enzyme ALDH is a useful marker for normal and malignant breast stem cells.[13] ALDH also can be used to isolate breast cancer stem cells from human tissue. Jolicoeur and colleagues found that ALDH tends to be expressed on basal-type rather than luminal-type breast cancers.[14] These researchers studied formalin-fixed, paraffin-embedded specimens from 57 patients with breast cancer. The samples were assessed with immunohistochemistry for ALDH-1 as well as the estrogen and progesterone receptors (ER and PR, respectively) and HER-2. Basal cell markers investigated included epidermal growth factor receptor (EGFR)-1, CK5, CK14, CK17, and smooth muscle alpha-actin (SMA); luminal cell markers included CK19 and epithelial membrane antigen (EMA).
These investigators found that breast cancer specimens that were triple negative (ie, negative for ER, PR, and HER-2) and also expressed at least one basal cell marker were more likely to be positive for ALDH-1 staining. These findings suggest that basal cancers may arise from primitive mammary stem cells. At least some of the luminal cancers (which have a more favorable prognosis) are not as likely to express ALDH. These findings support the concept that different molecular subcategories of breast cancer may be derived from different cells and may express distinct markers.
Other markers that have been used to identify breast cancer stem cells include CD44 positivity and CD24 negativity.[1] It has been relatively difficult to identify these markers using immunohistochemistry. According to study findings presented at SABCS, however, Rimm and colleagues used the fluorescent AQUA [automated quantitative analysis] technique[15] to combine ALDH staining with CD44 expression and demonstrated that ALDH-positive CD44 cells correlated with a poor prognosis. On the basis of their findings, they suggest that combining ALDH and CD44 may be superior to use of either marker alone for the detection of breast cancer stem cells.
Medscape: What are some other important issues with respect to stem cells in breast cancer?
Dr. Wicha: A study by Latimer and colleagues suggests that racial differences in breast carcinogenesis may relate in part to the differences in the ability of breast stem cells to differentiate in white vs African-American women.[16] African-American women are more likely to die from breast cancer, and the incidence of breast cancer is higher in African-American women under 40 years of age compared with white women of the same age. With use of a mammary tissue module, these researchers found that race was a modifying factor in the ability of cells to form ductal structures in vitro, which significantly increased the rate of differentiation. They suggest that if breast tissue from African-American women has a more robust differentiation potential than that of white women, it may also contain more stem cells, associated with an aggressive tumor type. In addition, our group has found different frequencies of ALDH positivity in African-American women compared with white populations. Together, these studies may provide a partial explanation for the increased incidence of breast cancer in African-American women.
Medscape: Do you think that the key stem cell markers have been identified, or do several stem cell markers remain to be found?
Dr. Wicha: The field of cancer stem cell research is in its early stages. It is going to be very important to search for more stem cell markers, particularly for luminal breast cancers. We currently have effective markers for identifying stem cells in basal breast cancers, but it is becoming clear that luminal breast cancers may be driven by different stem cells.
Another important question exists regarding the relationship of HER-2 expression and cancer stem cells. Our laboratory has recently shown that HER-2 overexpression increases cancer stem cell frequency. This finding is also consistent with our clinical data that show an increase in ALDH-positive cells in HER-2-positive breast cancers. The remarkable efficacy of agents such as trastuzumab and lapatinib in treating metastatic and early-stage breast cancer may relate to the fact that these agents are able to target breast cancer stem cells. Mechanisms of trastuzumab resistance as well as the question of whether trastuzumab can benefit women without HER-2-amplified tumors are open questions that need further investigation.
Medscape: How far away is the application of these findings in clinical practice?
Dr. Wicha: Cancer stem cell research is still in its infancy. However, use of stem cell inhibitors such as gamma secretase inhibitors to inhibit Notch signaling or Hedgehog inhibitors is currently being investigated in early-phase clinical trials. Neoadjuvant trial designs such as those reported by Dr. Jenny Chang at Baylor College of Medicine in Houston, Texas, will provide important new information on the ability of these agents to specifically target breast cancer stem cells.[5] In these studies, it will also be important to measure the effect of treatment on stem cell markers as well as on the pathways that drive cancer stem cells.
This activity is supported by an independent educational grant from Susan G. Komen for the Cure.
References
[ CLOSE WINDOW ]
References

  1. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983-3988. Abstract
  2. Chen MF, Lin CT, Chen WC, et al. The sensitivity of human mesenchymal stem cells to ionizing radiation. Int J Radiat Oncol Biol Phys. 2006;66:244-253. Abstract
  3. Wicha MS. Identification of murine mammary stem cells: implications for studies of mammary development and carcinogenesis. Breast Cancer Res. 2006;8:109.
  4. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672-679. Abstract
  5. Chang JC, Li X, Creighton C, et al. Decrease in tumorigenic breast cancer stem cells -- final results of a neoadjuvant trial in primary breast cancer patients. Program and abstracts of the 6th European Breast Cancer Conference (EBBC); April 15-19, 2008; Berlin, Germany. Abstract 204
  6. Korkaya H, Paulson A, Iovino F, Wicha MS. HER-2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27:6120-6130. Abstract
  7. Wicha M. Molecular targets in breast cancer stem cells. Program and abstracts of the 31st Annual San Antonio Breast Cancer Symposium (SABCS); December 10-14, 2008; San Antonio, Texas. Basic Science Panel Discussion.
  8. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557-563. Abstract
  9. Beider K, Abraham M, Peled A. Chemokines and chemokine receptors in stem cell circulation. Front Biosci. 2008;13:6820-6833. Abstract
  10. Dontu G. Breast cancer stem cell markers -- the rocky road to clinical applications. Breast Cancer Res. 2008;10:110.
  11. Honeth G, Bendahl PO, Ringnér M, et al. The CD44+/CD24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10:R53.
  12. Aktas B, Tewes M, Hauch S, Fehm T, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial-mesenchymal transition markers on circulating tumor cells in patients with metastatic breast cancer. Cancer Res. 2009;69(suppl 2):84s. Abstract 107.
  13. Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555-567.
  14. Jolicoeur F, Garcia de la Fuente I, Gaboury L, Balicki D. ALDH1 is a useful marker of basalness in human breast cancer and its stem/progenitor cells. Cancer Res. 2009;69(suppl 2):83s. Abstract 104.
  15. Rimm DL, Barlow WE, Harigopal M, et al. Multiplexed AQUA-based assessment of SWOG 9313 shows prognostic value of continuous ER, PR and HER-2 assessment. Cancer Res. 2009;69(suppl 2):97s.
  16. Latimer JJ, Lalanne NA, Myers NT, Courtney AB, Mock L, Grant SG. A new paradigm for African American breast cancer involving stem cell differentiation. Cancer Res. 2009;69(suppl 2):324s. Abstract 5051.

Contents of Highlights of SABCS 2008 All sections of this activity are required for credit.
  1. Highlights in HER-2-Positive Breast Cancer
  2. Highlights in Adjuvant Endocrine Therapy for Breast Cancer
  3. Breast Cancer Stem Cells as Novel Therapeutic Targets: An Expert Interview With Dr. Max S. Wicha
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