Forbeck Focus Meeting 2001 - Mechanisms, Consequences, and Therapeutic Implications of Blood Vessel Leakiness in Cancer

October 4 - 7, 2001, Napa Valley, CA

Organizer:
Donald M. McDonald, MD, Ph.D., University of California, San Francisco, CA


Layout:

  1. Endothelial barrier function of normal vessels
  2. Mediators of endothelial leakiness
  3. Leakiness of tumor vessels: Abnormalities in endothelial cell and pericyte structure, function, & basement membrane
  4. Consequences of tumor vessel leakiness
  5. Genomic analysis of vascular targets
  6. Targeting of drugs to tumor vessels
  7. Therapeutic manipulation of tumor vessels
  8. Monitoring leakiness of tumor vessels

Focus:
This meeting will be the first of its kind focused on the pathophysiological and therapeutic implications of blood vessel leakiness in cancer. The fact that tumor vessels are leakier than normal vessels has been well documented in human cancer and in experimental tumor models. Vessel leakiness has been attributed to the dynamic aspects of tumor vessels and the rapid proliferation of endothelial cells, combined with the abnormal extracellular matrix of tumors. However, the cellular mechanism of the leakiness to rate of cancer growth, predisposition to metastasis, and delivery of macromolecular therapeutic agents to tumor cells have only begun to be examined using contemporary methodologies.

The purpose of this meeting is to bring together experts in the fields of cancer biology and vascular biology to identify experimental approaches that can determine why tumor vessels are leaky, whether the leakiness sis reversible, and if so, how the reversal would impact tumor growth, metastasis, and drug delivery. Despite major advances in the field of tumor angiogenesis, relatively little attention has been paid to the permeability of the newly formed vessels. This meeting would provide an opportunity for scientists who study blood vessel barrier function to join forces with scientists working on tumor angiogenesis, growth and metastasis.

A meeting on tumor vascular permeability would be timely and have multiple benefits. Several recent discoveries highlight the relevance and value of this topic. For example, (1) vascular endothelial growth factor (VEGF), which drives angiogenesis in some tumors, also causes plasma leakage. Plasma leakage produced by VEGF was recently found to be blocked by angiopoietin-1 (Ang1) and inhibitors or Src kinases. Although Src kinase inhibitors appear to be specific to VEGF-induced leakage, Ang1 blocks leakage produced by a variety of substances. If these inhibitors reduce tumor vessel leakiness, it would be possible to determine whether tumor growth and metastasis are promoted by leakiness. A potential therapeutic strategy based on the reduction in plasma leakage is among the topics to be discussed at this meeting. (2) In vivo microscopy and magnetic resonance imaging studies have shown that anti-VEGF antibody reduces the leakiness of tumor vessels before it decreases tumor size. Another topic to be discussed would be whether the reduction in leakage contributes to favorable responses to VEGF antagonists. (3) Other recent studies suggest that the heterogeneity of vessel leakiness within a tumor results from regional differences in production of VEGF or other factors. The periphery of tumors is one of the regions that tends to have especially leaky vessels and may favor tumor growth and metastasis. Vessel leakiness also governs the access of therapeutic antibodies, gene therapy vectors, and liposomal drug delivery systems to tumor cells. Together, these recent discoveries make it timely to determine the relationship between the leakiness of tumor vessels and tumor growth and metastasis. A more thorough understanding of the causes, consequences, and therapeutic implications of tumor vessel leakiness will make it possible to test the importance of this phenomenon in disease progression and treatment.

Outcome Report: This meeting was the first of its kind focused on the significance of blood vessel leakiness in tumors. Despite major advances in the field of tumor angiogenesis, relatively little attention has been paid to the permeability of blood vessels in tumors. The leakiness of tumor vessels is well documented in experimental tumor models and in human cancer, but the cellular mechanism of the leakiness is poorly understood, and importantly, the implications of the leakiness to rate of cancer growth, predisposition to metastasis, and delivery of macromolecular therapeutics to tumor cells are at an early stage of understanding. Blood vessel leakiness not only influences the interstitial environment of tumors but also governs the access of therapeutic antibodies, gene therapy vectors, and liposomal drug delivery systems to tumor cells. Therefore, it is timely to determine the biological and clinical relevance of the leakiness of tumor vessels. This conference provided an opportunity for scientists who study blood vessel barrier function to join forces with scientists working on tumor angiogenesis and other areas of cancer biology to define the state-of-the-art in this field and to set out some directions for future research. The participants were charged with identifying what is known and what is not known about the field and to recommend experimental approaches that can help to reveal why tumor vessels are leaky, the consequences of the leakage, whether the leakage is reversible, and how the reversal would impact tumor growth, metastasis, and drug delivery.

Donald McDonald challenged the participants to consider the significance of the leakiness of blood vessels in tumors by addressing several questions: (1) Why are the blood vessels in tumors leaky and what are the consequences of the leakiness? (2) How can blood vessel leakiness be assessed in experimental tumors and in human cancer? (3) Would it be therapeutically beneficial to decrease the leak, and if so, how could this be achieved? (4)Would “normalization” of tumor blood vessel structure and function be beneficial in cancer therapy, and if so, how could this be done? (5) What strategies are available to target therapeutics to tumor vessels with the goal of normalizing or destroying the vessels?

At the end of the conference, all participants were asked to reflect on the presentations and discussions and summarize for this report some key questions to be addressed, experiments to be performed, and conclusions drawn about blood vessel leakiness in cancer.

The conference was energized by probing questions, lively discussion, and differing opinions. The participants discussed a broad range of issues, suggested many novel experiments, and drew insightful conclusions. At the end, many important areas for future research were in sharper focus.