Mechanisms, Consequences, and Therapeutic Implications of Blood Vessel Leakiness in Cancer

Donald M.
McDonald
,
MD, PhD
University of California, San Francisco

Forum Description

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.

Forum Summary

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.

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.

Venue & Travel Information

Travel Forms

TRAVEL FORMS DUE:
September 4, 2001
submit travel form

Travel Policy

Please familiarize yourself with our policies and procedures for travel. We truly appreciate you taking the time to participate in this meeting. As you make your plans, please remember that we are a nonprofit organization dependent on donations and volunteers. We do NOT pay for upgrades, change fees, incurred costs resulting from a flight change, transportation to or from your local (home side) airport, meals or other incidentals.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.
  • Spouses are welcome to come with you at their own cost but are not allowed to attend the meeting. Please no children.

What the Foundation Pays

Accommodations and meals are provided by the foundation during the meeting. Airfare will be covered only if booked through our travel agent. The Foundation will also cover airport transportation on the meeting side at the designated shuttle times. You can select not to utilize Foundation arranged transportation at your own expense when completing the travel form. Once your travel form is received your accommodations and airport transfer will be confirmed. Please let us know of any food allergies or other information we should be aware of on the travel forms.

  • If you would like your airfare covered by the Foundation, you must book with our travel agent. Note we do not cover upgrades, changes, late bookings, etc.
  • Flights must be booked at least 30 days prior to the meeting to confirm your accommodations and airport transfer.
  • As a nonprofit we utilize volunteers and other methods to maximize our efforts (or our donor support) when making accommodations and arranging ground transportation. Ground transportation will be provided upon your arrival either by a foundation volunteer or arranged shuttle. You will be provided airport transportation information the week of the meeting. We do not reimburse for home side airport transfer or incidentals while traveling.

Abstracts

Abstracts are due 30 days prior to the start of the meeting to allow enough time to prepare the meeting book.

The abstracts should be only one or two paragraphs outlining the theme of your presentation and should reflect the objective and spirit of the meeting (see above). Abstracts will be circulated about one week before the meeting. The meeting organizer will start requesting them a month before the meeting.

abstracts DUE:
September 4, 2001
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Meeting Structure

The meeting structure has been developed over years of experience.

  • Participants have approximately 45 minutes, depending on the number of participants, for their presentation and discussion. The presentation is meant as a conversation start and should last about twenty minutes briefly covering background information and areas that are new or need further input. This should be structured in such a way as to lead to a lively discussion. Participants are encouraged to interrupt to ask questions or start discussions.
  • A MAXIMUM of 5 slide equivalents per presentation is allowed (Power point slides should not contain more than one graph or gel per slide and no more than 5 bullet points to stress the points being made by the presenter.) We appreciate cooperation with the spirit of this guideline. Handouts are welcome but should be distributed before sessions.
  • Everyone is expected to actively participate in every session and discussions.
  • The time spent at the meeting is relatively short, so please be familiar with papers received prior to the meeting.
  • It is very important that you commit to all sessions of the 2 days of meetings.

Forbeck Scholars Participation

Scholars are selected for each Forbeck Forum. These are outstanding junior clinical or post-doctoral fellows selected based on the quality and relevance of science.

  • Scholars present for 30-45 minutes, depending on the number of participants
  • The same presentation rules apply for scholars
  • After the Forum you are selected to attend, you will attend three years of Scholar Retreats held in Lake Geneva, WI. If you attend a Fall Forum, you will attend the Spring Retreat. If you attend a Spring Forum you will attend a Fall Retreat.
  • Scholars are selected by the Foundation Scientific Advisory Board and peer reviewers selected from past Forbeck Scholars.

General Program

The outline below illustrates a typical program schedule. You will receive a complete schedule, including speaking times, the Thursday the meeting starts.

Arrival Day
1:00 PM Arrivals
6:00 PM Cocktails (opt'l)
7:00 PM Dinner
Meeting Day 1
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Meeting Day 2
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Departure Day
7:00 AM Breakfast
8:00 AM Departures

Frequently Asked Questions

Below are some of our most Frequently Asked Questions. If you have something new to ask, please feel free to contact us.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • Frequently airport transfer is provided by volunteers. Please be patient on receiving this information. Airport transfer will be sent out prior to arrival.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.

Forum Participants

Participant List Coming Soon

Forum Scholars

No Scholars attended this meeting