The problem that won't go away

The New York Times today focuses on the difference between Stage 4 and other breast cancers, under an unfortunate headline: "A Pink-Ribbon Race, Years Long." Note to all: Editors, not reporters write the headlines.

The lead is about a woman with metastasis who went to a support group meeting and didn't have the heart to tell the rest of the women, who had stages 1-3, about herself. I was what scared them, the woman, Suzanne Hebert, said.

Let's look at the numbers: some 40,000 people in the US die of breast cancer a year. About a quarter of us who are first diagnosed with early-stage breast cancer end up with metastasis. About 150,000 are living with Stage 4.

The story quotes Dr. Eric P. Winer, director of the breast oncology center at the Dana-Farber Cancer Institute in Boston: All too often, when people think about breast cancer, they think about it as a problem, it’s solved, and you lead a long and normal life.

There was CJ, who was married to my old friend A. She was diagnosed in 2001, six years before I was, with about the same stage. She had a mastectomy, no need for chemo, her doctors said, and the family traveled and she continued working in an underfunded public school library on the East Coast, coaching the Reading Olympics team. Five years later the cancer came back. When I saw her a few years ago, she was getting treatment for cancer that had moved to her spine and brain. In spring 2009, she was losing her sight but still took the Reading Olympics kids to a competition. I didn't see her on a visit around then; I saw A when he drove me to the airport. One weekend in May 2009 she accused him of not turning on the lights. She went to school on Monday and realized that she really could not see and she quit. She died at home in August 2009.

I went to a funeral yesterday of an adult student who died suddenly at 46. She was an accomplished actor, playwright and teacher, and was in our MFA program to learn more about nonfiction writing. Last week she went home after our evening class, and she and her husband had some wine and were watching some trashy TV to relax. He got up to get more wine, and when he came back, his wife wasn't breathing. Her heart stopped before the paramedics got there. A lingering illness, he said, that would have been preferable. I think both are bad, I said. My friend S, who was close to the couple, said that at least with a lingering illness you can say goodbye, you can ask for advice. I don't know what A would say about that. Both ways have their down sides. I've long been against Death, but Death doesn't seem to care.
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Image above is Pandora [Jane Morris] by Rossetti, which doesn't really fit, except in mood

CSCs responsible for metastasis identified

Cancer stem cells responsible for metastasis identified: HK study, Xinhua News Agency, June 4, 2010. Excerpt:

Hong Kong researchers have identified a subset of cancer stem cells responsible for metastasis in human colorectal cancer which can help better predict the prognosis and design a more suitable treatment for patients, according to a study made public by the University of Hong Kong on Friday.

The researchers from the university's medicine school discovered that cancer stem cells with a surface marker CD26, which marks a subset of cancer stem cells with metastatic capacity, are present in all terminal colon cancer cells and all metastatic cancer cells.

This news item is about the publication: A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer by Roberta Pang and 13 co-authors, including Wai Lun Law, Ronnie T Poon and Benjamin CY Wong [photos of authors], Cell Stem Cell 2010(Jun 4); 6(6): 603-15. [Summary][Twitter entry][Commentary][FriendFeed entry][Science Pond entry].

CD133 expression has high prognostic impact for colon cancer

The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer by David Horst and 6 co-authors, including Thomas Kirchner and Andreas Jung, J Pathol 2009(Jun 25) [Epub ahead of print] PubMed Abstract:

In colon cancer, CD133 has recently been used to enrich for a subset of tumour cells with tumour-initiating capabilities and was therefore suggested to mark colon cancer stem cells. However, this molecule has surprisingly been shown to lack functional importance for tumour initiation itself. Herein, we investigated whether CD133 may be relevant for colon cancer metastasis in patients, and as metastasis requires several additional biological characteristics besides tumour initiation, we examined the effects of knocking down CD133 expression in colon cancer cell lines on proliferation, migration, invasion, and colony formation. We demonstrate that high CD133 expression correlates strongly with synchronous liver metastasis in a matched case-control collection, while siRNA-mediated knock down of this factor has no significant effect on the mentioned biological characteristics. Thus, we conclude that CD133 expression is a marker with high prognostic impact for colon cancer, while it seems to have no obvious functional role as a driving force of this malignancy.

Differentially expressed genes in cell lines of differing lymphatic metastatic ability

Lymphatic metastasis of breast cancer cells is associated with differential gene expression profiles that predict cancer stem cell-like properties and the ability to survive, establish and grow in a foreign environment by Terlika S Pandit and 11 co-authors, including Ann F Chambers and Alan B Tuck, Int J Oncol 2009(Aug); 35(2): 297-308. [FriendFeed entry]. PubMed Abstract:

Although lymphatic dissemination is a major route for breast cancer metastasis, there has been little work to determine what factors control the ability of tumor cells to survive, establish and show progressive growth in a lymph node environment. This information is of particular relevance now, in the era of sentinel lymph node biopsy, where smaller intranodal tumor deposits are being detected earlier in the course of disease, the clinical relevance of which is uncertain. In this study, we compared differentially expressed genes in cell lines of high (468LN) vs. low (468GFP) lymphatic metastatic ability, and related these to clinical literature on genes associated with lymphatic metastatic ability and prognosis, to identify genes of potential clinical relevance. This approach revealed differential expression of a set of genes associated with 'cancer stem cell-like' properties, as well as networks of genes potentially associated with survival and autonomous growth. We explored these differences functionally and found that 468LN cells have a higher proportion of cells with a cancer stem cell-like (CD44+/CD24-) phenotype, have a higher clonogenic potential and a greater ability to survive, establish and grow in a foreign (lymph node and 3D Matrigel) microenvironment, relative to 468GFP cells. Differentially expressed genes which reflect these functions provide candidates for investigation as potential targets for therapy directed against early lymphatic metastasis.

Lecture on stem cells and cancer

The 2009 Summer Symposium of the David H. Koch Institute for Integrative Cancer Research of MIT was on Understanding Metastasis. The Symposium was held on June 19, 2009. One of the lectures in the morning session was on "Stem cells and cancer", by Sean Morrison (University of Michigan) [FriendFeed entry]. A video (35 min) of the lecture can be accessed via the program. One example of a noteworthy slide is the one that's shown for 10 seconds, from 28:38 to 28:48 (entitled: "Nobody has yet tested which cells actually contribute to disease in patients"), in which it's pointed out that the "Fate of cells within patients is unclear ...".

Another lecture, at the same Symposium, addresses this issue (within the context of the theme of the Symposium, "Understanding Metastasis"). It's "Monitoring the fate of cancer cells during metastasis", by Ann Chambers (Regional Cancer Center, London, Ontario). A video (25 min) of her lecture can also be accessed via the program.

Breast Reconstruction in Metastatic Breast Cancer Patients

Traditional medical opinion states that women with metastatic breast cancer are not candidates for breast reconstruction. Once metastases are diagnosed (stage 4 breast cancer), attention turns solely to aggressive medical treatment to prolong life. Breast reconstruction is no longer discussed as an option.

At least that was the consensus up until fairly recently.

Opinions have started to change over the last few years. 

While we are still losing the battle with stage 4 breast cancer and most women will die from their disease, who are we to decide that these women should not be made "whole"? Why should any women interested in breast reconstruction die breastless?

As long as patients interested in reconstruction  are medically stable and passed "fit for surgery", the psycho-social and quality of life benefits that breast reconstruction can provide should not be ignored. While the priority must always remain "life over breast", breast reconstruction should be discussed with patients regardless of the stage of the disease.

Dr C

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Dr Chrysopoulo is a board certified plastic surgeon specializing in breast reconstruction surgery after mastectomy using the patient's own tissue. PRMA Plastic Surgery, San Antonio, Texas. Toll Free: (800) 692-5565. Keep up to date with the latest news in breast reconstruction surgery and research at The Breast Cancer Reconstruction Blog.

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Cancer stem cells, hypoxia and metastasis

Cancer stem cells, hypoxia and metastasis, Richard P Hill, Delphine T Marie-Egyptienne, David W Hedley, Semin Radiat Oncol 2009(Apr);19(2):106-11. Abstract:

The successful growth of a metastasis, by definition, requires the presence of at least 1 cancer stem cell. Metastasis is a complex process, and an important contributor to this process is the influence of the tissue microenvironment, both cell-cell and cell-matrix interactions and the pathophysiologic conditions in tumors, such as hypoxia. A number of studies have suggested that normal stem cells may reside in “niches,” where cell-cell and cell-matrix interactions can provide critical signals to support and maintain the undifferentiated phenotype of the stem cells. In this article, the evidence that these niches may be hypoxic is described, and the potential role that hypoxia may play in maintaining the stem cell phenotype in cancers is discussed. Recent work has suggested that there may be a linkage between the stem cell phenotype and that induced by the process of epithelial-mesenchymal transition (EMT). EMT plays an important role in cell movement and organ formation during embryogenesis, and it is currently hypothesized to be a major mechanism by which epithelial cancers may generate cells that can form metastases. Recent evidence suggests that the expression of certain genes involved in EMT is influenced by low oxygen levels, again suggesting a linkage between stem cells and hypoxia. Whether this supposition is correct remains an open question that will only be answered by further experimentation, but the potential role of hypoxia is critical because of its widespread existence in tumors and its known role in resistance to both radiation and drug treatment.

Chemokines in cancer and metastatic progression

The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis by Stefania Gelmini and 4 co-authors, including Elena Lazzeri, J Endocrinol Invest 2008(Sep); 31(9): 809-19 [PDF]. PubMed Abstract:

Chemokines exert their multifunctional role in several physiologic and pathologic processes through interaction with their specific receptors. Much evidence have revealed that metastatic spread tumor cells may use chemokinemediated mechanisms. In particular, an involvement of stromal cell-derived factor-1 (SDF-1) in growth of primary tumors and in metastatic process has been demonstrated. Indeed, it has been suggested that CXCR4 expression by tumor cells, plays a critical role in cell metastasis by a chemotactic gradient to organs expressing the ligand SDF-1. Moreover, CXCR4 overexpression correlated with poor prognosis in many types of cancer. In physiologic condition, SDF-1 also plays an essential role modulating stem cell proliferation, survival, and homing through its canonical receptor CXCR4. Recently, several studies have demonstrated the existence of a small subset of cancer cells which share many characteristics with stem cells and named cancer stem cells (CSC). They constitute a reservoir of self-sustaining cells with the ability to maintain the tumor growth. In particular, most of them express CXCR4 receptor and respond to a chemotactic gradient of its specific ligand SDF-1, suggesting that CSC probably represent a subpopulation capable of initiating metastasis. This review focuses on the role of SDF-1/CXCR4 axis in cancer and in the metastatic progression by tumoral cells, as well as the role of CSC in tumor pathogenesis and in metastatic process. A better understanding of migratory mechanism involving cancer cells and CSC provides a powerful tool for developing novel therapies reducing both local and distant recurrences.

Breast cancer stem cells hard to kill?

Breast cancer stem cells may be hardest to kill by John Miner, The London Free Press, October 11, 2008. (Archived by WebCite^® at http://www.webcitation.org/5bgoyZhVX). The first two paragraphs:

A London researcher is investigating the possibility that the most dangerous breast cancer cells also are the hardest to kill with chemotherapy and radiation.

Alysha Croker, a trainee at the Lawson Health Research Institute, and graduate student at the University of Western Ontario, has already established cancer cells within a tumour can play different roles.

The article appears to be based on a press release: "Bright, Young Minds at Lawson Fight Breast Cancer" [PDF] from the Lawson Health Research Institute (London, Ontario, Canada) dated September 10, 2008. The first paragraph:

The future of breast cancer treatment may involve targeting cancerous stem-like cells (cancer stem cells). These cancer stem cells have recently been identified as the cells that initiate and maintain tumor growth. The same cells seem to play a key role in breast cancer metastasis. What is more, these cells may be resistant to both radiation and chemotherapy. Alysha Croker, a trainee at Lawson Health Research Institute (Lawson) and a graduate student at the Schulich School of Medicine & Dentistry at The University of Western Ontario (Western), has been awarded a fellowship from the Canadian Breast Cancer Foundation (CBCF) to investigate the behaviour and response of cancer stem cells to commonly used chemotherapy agents and to radiation.

The Canadian Breast Cancer Foundation (CBCF) "allocates funds to high-quality research and community grants" across Canada.

Alysha Croker has worked under the guidance of Alison L Allan, an Oncology Scientist at the London Regional Cancer Program. For a recent review based on their work, see: Cancer stem cells: implications for the progression and treatment of metastatic disease by Alysha K Croker and Alison L Allan, J Cell Mol Med 2008(Apr); 12(2): 374-90. On October 19, 2008, both the HTML and PDF versions of the full-text were freely accessible. The PubMed Abstract:

Metastasis is the major cause of death for cancer patients with solid tumours, due mainly to the ineffectiveness of current therapies once metastases begin to form. Further insight into the biology of metastasis is therefore essential in order to gain a greater understanding of this process and ultimately to develop better cancer therapies. Metastasis is an inefficient process, such that very few cells that leave a tumour successfully form macrometastases in distant sites. This suggests that only a small subset of cells can successfully navigate the metastatic cascade and eventually re-initiate tumour growth to form life-threatening metastases. Recently, there has been growing support for the cancer stem cell (CSC) hypothesis which stipulates that primary tumours are initiated and maintained by a small subpopulation of cancer cells that possess "stem-like" characteristics. Classical properties of normal stem cells are strikingly reminiscent of the observed experimental and clinical behaviour of metastatic cancer cells, including an unlimited capacity for self renewal; the requirement for a specific 'niche' or microenvironment to grow; use of the stromal cell-derived factor 1 (SDF-1)/chemokine receptor 4 (CXCR4) axis for migration; enhanced resistance to apoptosis and an increased capacity for drug resistance. Therefore, in addition to playing a role in primary tumour formation, we believe that CSCs are also key players in the metastatic process. We will review the current evidence supporting this idea and discuss the potential implications of the CSC hypothesis with regards to experimental investigation and treatment of metastatic disease.

The Journal of Cellular and Molecular Medicine is published by Wiley-Blackwell, which offers a hybrid Open Access option called OnlineOpen. For 2008, the OnlineOpen fee is US$3000. See also the Journal of Cellular and Molecular Medicine Open Access Exclusive Licence Form [PDF].

Delayed OA, after an embargo period, is also available free of charge. According to the Journal of Cellular and Molecular Medicine Exclusive Licence Form [PDF], "12 months after publication you may post an electronic version of the Article on your own personal website, on your employer’s website/repository and on free public servers in your subject area" but "you are not permitted to post the Blackwell Publishing PDF version of the Article online". Some Wiley-Blackwell journals make their backfiles openly accessible after an embargo period (usually, a year or more), but the Journal of Cellular and Molecular Medicine isn't included in the current list of such journals. (See the section entitled "Wiley-Blackwell Open Access Backfiles" in the page entitled "Wiley-Blackwell and Open Access").

Added October 20, 2008:

See also another recent article: High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability by Alysha K Croker and 6 co-authors, including Alison L Allan, J Cell Mol Med 2008(Aug 4). [Epub ahead of print]. [PubMed Abstract]. A PDF version of the full text of this article is currently freely accessible.

Cancer spread and stem cells

There's an article, "Breakthroughs seen in cancer spread and stem cells", by Carey Goldberg of The Boston Globe, September 9, 2008. Excerpts from the first page:

Mani and his colleagues at the MIT-affiliated Whitehead Institute found what appears to be a key to metastasis, the insidious process by which cancer spreads throughout the body and often kills. And, in a surprising spinoff, that same discovery also may lead to a relatively safe, simple way to transform normal adult cells into stem cells that could be used to treat other diseases.

The scientists believe their one-step method may avoid the risk of random mutation (and possibly cancer), a stumbling block for therapies based on other recently developed techniques for creating stem cells.

Excerpts from the second page of the same article:

For all his excitement, Weinberg readily acknowledged that Mani's line of investigation has yet to produce a "gold-standard proof" that the stem-like cells are actually stem cells. If their thinking is correct, he said, it should be possible to induce the key metamorphosis in some breast cells of one mouse, place them in another mouse's chest and develop a breast.

The experiment worked once, he said, but his lab has been unable to replicate it and ended up publishing its work in the leading biology journal Cell this May without that crowning proof.

The publication in Cell isn't cited, but it appears to be this one: "The epithelial-mesenchymal transition generates cells with properties of stem cells", by Sendurai A Mani and 14 co-authors, including Robert A Weinberg, Cell 2008(May 16); 133(4): 704-15 [PubMed Abstract]. Unfortunately, the publication isn't freely accessible.

It's been cited by a more recent article (also not freely accessible): "Epithelial-mesenchymal transition and the stem cell phenotype", by Derek C Radisky and Mark A LaBarg, Cell Stem Cell, 2008(Jun 5); 2(6): 511-2 [PubMed Abstract]. The Abstract:

Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells acquire the motile, migratory properties of mesenchymal cells. In a recent issue of Cell, Mani et al. (2008) show that induction of EMT stimulates cultured breast cells to adopt characteristics of stem cells.

A brief excerpt from the full text:

An exciting implication of these results is that there may be a direct relationship between EMT and the phenomenon of CSCs.

Comments on these articles would be welcomed.