The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the “Seed” and the “Soil”?

International Journal of Breast Cancer, Nov 2011

Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic microenvironments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic microenvironments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation.

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The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the “Seed” and the “Soil”?

The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the “Seed” and the “Soil”? Jenny E. Chu1,2 and Alison L. Allan1,2,3,4 1Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 3K7 2London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada N6A 4L6 3Department of Oncology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 4L6 4Lawson Health Research Institute, Cancer Research Laboratories, London, ON, Canada N6A 4V2 Received 15 July 2011; Accepted 19 September 2011 Academic Editor: Lalita Shevde Copyright © 2012 Jenny E. Chu and Alison L. Allan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic microenvironments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic microenvironments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation. 1. Introduction Due to the expanding and aging global population, it is no surprise that cancer incidence and mortality are increasing despite ongoing research in the areas of cancer treatment and prevention. In North American women, breast cancer represents the most commonly diagnosed and the second highest cause of cancer-related deaths [1, 2]. Although the collection of exact global cancer statistics is difficult due to differences in healthcare infrastructure and data collection methods, the GLOBOCAN study ranks breast cancer as the most frequently diagnosed and the most prevalent cause of cancer-related death among women globally [3]. In the past, breast cancer has been a higher burden in developed countries, likely due to more risk factors associated with lifestyle such as postponement of pregnancy until after 30, less breast-feeding, smaller families, and a less active workplace [4]. It is predicted that as developing countries improve their economic conditions and adopt a more “westernized” lifestyle, incidence rates will increase [5]. The challenge then presents itself: what is the best way to target this lethal disease in developed countries while also counteracting the predicted increase in mortality in developing countries? The answer lies in the understanding of metastatic disease, the most lethal aspect of breast cancer. 2. Metastasis Even though advances have been made in prevention, detection, and treatment, the mortality rate associated with breast cancer has remained high [3]. Primary breast tumors originate within the lobule or duct of the breast, and therapies are highly efficient if the neoplasm is detected while localized within the original structure (in situ) or even still localized within the breast itself [6]. Therapeutic efficacy is greatly reduced once the cancer acquires invasive and metastatic properties. Therefore, metastatic disease represents the aspect of breast cancer responsible for the majority of breast-cancer-related mortalities. Following successful angiogenesis at the primary tumor site, the stepwise process of metastasis has been clearly defined. During the initial stage, cells escape from the primary tumor into the blood and/or lymphatic system via a process called intravasation. Once in the circulation, these cells must survive until they reach a secondary site where they arrest and enter the tissue (extravasation). Tumor cells able to initiate and maintain colony growth in these secondary sites form micrometastases which, following angiogenesis, grow into clinically detectable macrometastases [7–9]. 3. Metastatic Theories Clinical observations highlight that different cancers exhibit characteristic sites for secondary metastases that are dependent on the origin of the primary tumor, a phenomenon termed organ tropism [10, 11]. For example, breast cancer preferentially spreads to the lymph nodes, lung, liver, bone, and brain, while other primary cancers have diffe (...truncated)


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Jenny E. Chu, Alison L. Allan. The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the “Seed” and the “Soil”?, International Journal of Breast Cancer, 2011, 2012, DOI: 10.1155/2012/209748