21. FUTURE PERSPECTIVES
AND UNANSWERED QUESTIONS ON CANCER METASTASIS
AND THE LYMPHOVASCULAR SYSTEM
STANLEY P. L. LEONG AND MARLYS H. WITTE*
University of California San Francisco, San Francisco, California, USA,
*Department of Surgery, University of Arizona,Tucson, Arizona, USA
INTRODUCTION
For the clinical oncologist, the most humbling experience is when the cancer has spread and the disease is unresponsive to available therapy to curb progression. Paget developed the “seed and soil” hypothesis to explain the phenomenon of clinical cancer metastasis (1). Since the work of Paget, we have seen explosive advances in biological understanding of the mechanisms of metastasis. Numerous animal mod- els have been applied to further understand the cellular and molecular mechanisms of cancer metastasis (2). But the translational link to the clinic from such basic science advances continues to remain elusive. It is important, therefore, to bring cli- nicians and basic scientists together to share their knowledge and perspectives on the phenomena surrounding cancer metastasis. For this reason, the first International Symposium on Cancer Metastasis and the Lymphovascular System was organized and successfully held in San Francisco in April 2005. The meeting highlights have been summarized in the June issue of 2006 Cancer Metastasis Reviews.
294 Cancer Metastasis and the Lymphovascular System
HISTORICAL BACKGROUND (3)
Since the 1890s and the work of physiologist Ernest Starling and embryologist Florence Sabin, substantial understanding has been gained on the anatomy, devel- opment, and physiology of the lymphovascular system. During the past two decades, further knowledge has accumulated in these areas and also in the cellular and, most recently, molecular aspects of the lymphovascular system. Using the melanoma and breast cancer models from the sentinel lymph node (SLN) era, it has been learned that about 80% of the time, metastasis from the primary site fol- lows an orderly pattern of progression through the lymphatic network initially, whereas about 20% of the time systemic metastasis occurs without evidence of lymphatic invasion.
UNANSWERED QUESTIONS
Further progress is needed in unraveling the multifaceted aspects of micrometas- tasis including development of metastatic clones from the primary tumor site through proliferation and differentiation, acquisition of the surface molecules by the cancer cells to spread through either the lymphatic or blood vascular systems, and the host interaction with the invading cancer cells, so that more rational ther- apy can be developed to overcome these steps of progression from the primary site to the metastatic sites. Although the clinical patterns of cancer metastasis are well documented for many different types of cancer, the proximate molecular events linking each step from proliferation of the cancer within the tissue microenvironment to lymphatic or vascular invasion and widespread dissemina- tion are not well understood. Recent studies suggest that stem cells (4–7) within the proliferating cancer cell population are the primary subset that metastasize from the tumor bulk, which continues to grow locally without subsequent spread.These stem cells need to be better characterized with respect to their phe- notypic, genetic, and molecular profiles so that they can be selectively targeted for specific therapeutics.
On the other hand, the mechanisms of initiation and stimulation of lymphatic and blood vascular growth (both lymphangiogenesis and hemangiogenesis) within and around the tumor should be better understood (3); antiangiogenic therapy has already been used for specific molecular targeting. Can lymphangiogenesis be blocked as a therapeutic strategy? The functional role of SLNs and regional lymph nodes relating to cancer metastasis remains a crucial issue. Do the SLNs initially launch an immune response to the cancer cells and subsequently succumb to the invading cancer cells?
Tumor antigenic changes during metastasis should be further examined, whether these changes may result in tolerance of specific immune cells, allowing cancer cells to escape immune attack. New and improved technologies should be developed for dynamic noninvasive high resolution multimodal imaging to elucidate the micro- scopic and macroscopic events taking place in the lymphatic system during cancer development and spread. These techniques can form the basis for image-guided
21. Future Perspectives and Unanswered Questions 295
lymphatic-lymph node directed monitoring and selective treatment as molecular and cell-based therapies are developed. New approaches using nanoparticles to identify limited tumor burden should be explored (8). Molecular targeting against molecules involved in proliferation signaling pathways and apotosis may provide potential sites of intervention.
The recent identification of molecules on endothelial cells lining the lym- phatic channels (3, 9) paves the way for future studies to analyze the important issue whether cancer cell entry into the lymphatic channels is an active vs. a passive process or both. If passive processes are involved, what are the influences of mechanical factors and anatomical structures on the facilitation of cancer cell transport through the lymphatic channel (Chap. 10). If the active process is operative, what are the endothelial cell receptor mechanisms operating between the cancer cell and the molecules of the lymphatic channels and the lining endothelial cells?
ONCOLYMPHOLOGY
This newly opening active field of so-called oncolymphology needs to be vigor- ously pursued. When the foregoing mechanisms and events are more fully under- stood, can new therapeutic strategies be developed to curb these processes? The development of nanotechnology is highly promising both from the imaging point of view for the detection of early metastatic foci and in the delivery of new nanoparticulate agents to these sites with more efficiency.
These important issues and questions and much else we do not know about cancer and the lymphatic system (10) will be addressed in our upcoming Second International Symposium on Cancer Metastasis and the Lymphovascular System:
Basis for Rational Therapy to be held again in San Francisco from May 3–5, 2007.
The thrust of the upcoming symposium is once more to bring basic and clinical scientists together on an international level to address these challenging issues of cancer metastasis, forge collaborations, and translate basic science advances to improve the outlook of patients with cancer.
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