Sharon A. Vantyghem

Tumor Dormancy and Cancer Stem Cells: Implications for the Biology and Treatment of Breast Cancer Metastasis

Breast cancer remains a leading cause of morbidity and mortality in women, mainly due to the propensity of primary breast tumors to metastasize to regional and distant sites. Metastatic spread after the removal of a primary tumor can be difficult to identify, creating uncertainty in patients with regards to possible cancer recurrence. This is a particular problem in breast cancer, exemplified by the fact that recurrence can take place after decades of apparent disease-free survival. The mechanisms underlying tumor dormancy in breast cancer remain poorly understood, and this presents significant challenges to both experimental investigation and clinical management of breast cancer. This review will discuss what is currently known about the metastatic process and tumor dormancy, consider the growing evidence that cancer stem cells may contribute to tumor progression and dormancy, and speculate about the clinical importance and implications of this research.

Dietary Genistein Reduces Metastasis in a Postsurgical Orthotopic Breast Cancer Model

Metastatic spread, not primary tumor burden, is the leading cause of breast cancer deaths. For patient prognosis to improve, new systemic adjuvant therapies that are capable of effectively inhibiting the outgrowth of seeded tumor cells after surgical treatment of the primary breast tumor are needed. To facilitate the preclinical development of such therapies, relevant animal models of breast cancer metastasis that can mimic the postsurgical adjuvant setting are required. Here we developed a preclinical xenograft model of breast cancer metastasis where the primary tumor was removed by surgical resection before systemic adjuvant treatment. We used this model to assess the antimetastatic effect of postsurgical dietary intervention with the soy isoflavone genistein. The anticancer activity of genistein has been established in vitro and in vivo, however, few studies have tested the potential of genistein as an antimetastatic therapy. Using our model, we tested the efficacy of adjuvant treatment with genistein to inhibit the outgrowth of metastases postsurgery. To establish primary tumors, human breast carcinoma cells, MDA-MB-435/HAL, were implanted into the mammary fat pad of female nude mice. Primary tumors were left to grow for 5 weeks before being surgically removed. Mice were then randomized into two diet groups: control soy-free diet versus genistein-supplemented diet. Five weeks later, metastatic burden was assessed. Genistein reduced the percent metastatic burden in the lungs by 10-fold. These results indicate that dietary intervention following cancer surgery can affect the outgrowth of seeded tumor cells. The availability of well-characterized, clinically relevant animal models for studying factors that regulate metastatic outgrowth postsurgery will provide an important tool for developing new systemic adjuvant therapies.

Detection and quantification of circulating tumor cells in mouse models of human breast cancer using immunomagnetic enrichment and multiparameter flow cytometry

Circulating tumor cells (CTCs) in the peripheral blood of breast cancer patients may be an important indicator of metastatic disease and poor prognosis. However, the use of experimental models is required to fully elucidate the functional consequences of CTCs. The purpose of this study was to optimize the sensitivity of multiparameter flow cytometry for detection of human tumor cells in mouse models of breast cancer.

Molecular mechanisms of metastasis.

A major topic covered at the First International Symposium on Cancer Metastasis and the Lymphovascular System was the molecular mechanisms of metastasis. This has become of major interest in recent years as we have discovered new metastasis-related genes and gained understanding of the molecular events of lymphatic metastasis. The symposium covered new aspects and important questions related to the events of metastasis in both humans and animals. The basic and clinical related research covered in this topic represented many disciplines. The presentations showed novel findings and at the same time, raised many new unanswered questions, indicating the limited knowledge we still have regarding the molecular events of metastasis. The hope is that further unraveling of the direct and indirect molecular events of lymphatic metastasis will lead to new approaches in developing effective therapeutics.

A new model for lymphatic metastasis : Development of a variant of the MDA-MB-468 human breast cancer cell line that aggressively metastasizes to lymph nodes

Breast cancer often spreads from the primary tumor to regional lymph nodes. Lymph node status provides clinically important information for making treatment decisions. Spread via lymphatics is also important for the biology of breast cancer, as tumor cells in lymph nodes may provide a reservoir of cells leading to distant, lethal metastases. Improved understanding of the biology of lymphatic spread thus is important for improved breast cancer survival. Advances towards understanding the interactions between tumors cells and lymphatic vessels have in part been limited by the lack of suitable cell lines and experimental models. We have addressed this need by developing a new model of lymphatic metastasis. Here we describe the establishment of 468LN cells, a variant of the MDA-MB-468 human breast adenocarcinoma cell line, which produces extensive lymph node metastasis following orthotopic injection of nude mice. 468LN cells are also more aggressive in vitro, produce more osteopontin and express different surface integrins compared to the parent line. The dramatic in vitro and in vivo phenotypic and molecular differences of 468LN and parental 468GFP cells make this pair of cell lines a unique model for the specific study of lymph node metastasis of breast cancer.

Angiogenesis as a Target for Breast Cancer Therapy

Angiogenesis, the development of new bloodvessels, is crucial for the growth of both primarytumors and metastases beyond a minimal size and thevasculature of tumors facilitates their metastaticspread. Inhibition of angiogenesis is thus seen as apotentially useful approach to anti-metastasis therapy,and is an area of active research and development. Herewe discuss this therapeutic approach in the context of breast cancer. An overview of thecontribution of angiogenesis to tumor development isprovided and current treatment options for breast cancerare briefly summarized. Assessment of angiogenesis inprimary breast tumors has been shown to provideindependent prognostic information. There areopportunities for the application of anti-angiogenesistherapeutic strategies in the treatment of breastcancer. Clinical trial design must take into account the uniqueproperties of anti-angiogenic agents to fully assesstheir potential clinical benefit.