Ann Chambers, PhD

Ann Chambers

Distinguished Oncology Scientist: London Regional Cancer Program, London Health Sciences Centre, London, Ontario

Director: Pamela Greenaway-Kohlmeier Translational Breast Cancer Research Unit

Canada Research Chair in Oncology: Canada Research Chairs

Professor of Oncology: University of Western Ontario, London, Ontario

Cross Appointments: Medical Biophysics and Pathology

Mailing Address

London Regional Cancer Program
Room A4-903b
Cancer Research Laboratory Program
790 Commissioners Rd. E.
London, Ontario
Canada N6A 4L6

Tel: 519.685.8652
Fax: 519.685.8646
Email: ann.chambers@lhsc.on.ca

Research Area

Cell and molecular biology of metastasis

Summary of Current Work

Metastasis, the spread of cancer cells from a primary tumor to new sites, is a major factor in preventing successful treatment of cancer. Metastasis can occur after years of dormancy following treatment of a primary cancer. We are using experimental and clinical approaches to study metastasis and tumor dormancy. We have used in vivo videomicroscopy to clarify the steps and molecular mechanisms in metastasis. We have discovered that large numbers of dormant single cells may remain in secondary organs, with the potential to resume growth at later times to form metastases. Our research suggests that new anti-metastatic therapies should be directed against the site-specific growth of cancer cells after they have arrived in the new organ. We are collaborating with Dr. Paula Foster to use novel cellular magnetic resonance imaging approaches to study metastasis and tumor dormancy.

We also are studying how an oncogene-induced, integrin-binding protein called osteopontin (OPN) contributes to the growth and progression of many kinds of tumors. We have shown that OPN can function to promote malignancy of cells in culture, and we are studying how OPN affects tumor growth and progression. In clinical studies, we have shown that women with metastatic breast cancer have blood OPN levels that are higher than normal levels, and that OPN tissue levels are higher in lung, esophageal and breast tumors than in adjacent normal tissue. These experimental and clinical studies will clarify the role of OPN functionally in cancer, and its potential role as a prognostic indicator in breast and other cancers.

The overall aim of our research is to learn how cancer cells spread, in order that novel anti-metastasis therapies can be developed.

Current Projects

Molecular and Videomicroscopic analyses of Mechanisms of Cancer Metastasis

In collaboration with Drs. Alan Groom and Ian MacDonald of the Medical Biophysics Dept., we developed a novel procedure, intravital videomicroscopy (IVVM), for direct in vivo observation of steps in metastasis. We are using IVVM, as well as quantitative in vivo analytical tools that we have developed, to clarify the steps in metastasis and their molecular mechanisms. Our results suggest that early steps, e.g. hemodynamic destruction and extravasation (escape from the circulation) may contribute less to metastatic inefficiency than previously believed. Instead, tissue specific regulation of tumor cell growth in secondary sites appears to play a key role in regulation of metastasis. We have discovered that surprisingly large numbers of solitary cells may remain dormant in tissue for long periods of time, and these cells have the potential to re-grow to form metastases. This finding has led to ongoing studies on mechanisms of tumor dormancy. In addition, we have developed novel ways to measure tumor angiogenesis (growth of new blood vessels, required for tumor growth). Clinical implications of our findings include the possibility that large numbers of circulating cancer cells may extravasate and remain viable in secondary organs. This suggests that growth regulation of cancer cells in secondary sites may be a promising target for therapeutic intervention to prevent metastasis, either by inhibiting tumor cell growth directly or by inhibiting angiogenesis.

Role of Osteopontin (OPN) in Malignancy

OPN is produced by many malignant cells. We have shown that OPN can contribute functionally to malignancy; production of OPN antisense RNA markedly reduced malignancy of ras-transformed cells. We have prepared recombinant OPN which is functional in cell adhesion and chemotaxis assays. Using site-directed mutagenesis, we mutated the integrin-binding RGD amino acid sequence within OPN, and found that the mutated proteins lost functional activity, supporting the idea that integrin binding is crucial for its function. In collaboration with clinical colleagues, we are analyzing expression of OPN in human cancer tissues and in blood from patients with metastatic cancers. We found that blood OPN is elevated in women with metastatic breast cancer, and that higher OPN levels are associated with shorter survival. As part of studies to clarify the regulation of OPN in cancer, we identified a novel ras-activated enhancer in the OPN promoter, and have found that many metastatic cells produce a protein able to interact with this sequence. In collaboration with Dr. Alan Tuck of the Pathology Dept., we are studying the molecular mechanisms by which OPN influences the malignant properties of breast and other cancer cells.

PubMed Publications

See my publications on PubMed

View Publication (PDF)

Chambers AF, AC Groom and IC MacDonald. Dissemination and growth of cancer cells in metastatic sites. Nature Reviews Cancer 2: 563-572, 2002.

Key Collaborators

Alan B. Tuck, MD, PhD, FRCPC (Anatomic Pathology)
Assistant Professor: Departments of Pathology and Oncology, University of Western Ontario
Staff Pathologist: Department of Pathology, London Health Sciences Centre and St. Joseph's Health Centre

Dr. Tuck is a pathologist, specializing in breast pathology, whose clinical work is based at London Health Sciences Center and St. Joseph's Health Centre, also affiliated with the London Regional Cancer Program. He is a consultant in breast pathology for SW Ontario. Research interests include the cell and molecular biology of breast cancer, osteopontin, tumor metastasis, and early development of models for studying breast cancer progression. This research is translational in nature, with the goal of developing new tools/targets for the management of patients at different stages of breast cancer.

Alison Allan, PhD
Assistant Professor: Departments of Oncology, and Anatomy & Cell Biology, University of Western Ontario, London
Paula Foster

Robarts Research Institute, University of Western Ontario

Staff and Research Trainees

Overall interests of the laboratory are in mechanisms of tumor metastasis, angiogenesis, osteopontin, blood and tumor markers, in vivo videomicroscopy and other preclinical imaging modalities, breast cancer, and translational studies.

Research Associate:

Dr. Pieter Anborgh
Project: Experimental and clinical studies on the role of osteopontin in cancer
Email Dr. Pieter Anborgh

Postdoctoral Fellows:

Brigitte Goulet, PhD
Project: The role of nuclear maspin in breast cancer metastasis
Email Brigitte Goulet

Hon Sing Leong, PhD
Project: Novel imaging approaches for lymphatic metastasis
Email Hon Sing Leong

Graduate Students:

Jennifer MacLean, PhD Student, Department of Medical Biophysics
Co-supervisor: Dr. Ian MacDonald
Project: Potential role of Aprotinin in metastasis prevention
Email Jennifer Maclean

Mike Lizardo, PhD Student, Department of Medical Biophysics
Co-supervisor: Dr. Ian MacDonald
Project: Lymphatic metastasis in breast cancer
Email Mike Lizardo

Jennifer Mutrie, MSc Student, Department of Pathology
Co-supervisor: Dr. Alan Tuck
Project: Osteopontin mediated molecular pathways and their response to specific inhibitors
Email Jennifer Mutrie

Lesley Souter, PhD Student, Department of Pathology
Co-supervisor: Dr. Alan Tuck
Project: Modeling of early breast cancer progressing in vitro and in vivo
Email Lesley Souter

Research Technicians:

Joseph Andrews, BSc, MSc, Research Technician
Specialty: Microarray technology, molecular biology; methylation studies (with Dr. David Rodenhiser)
Email Joseph Andrews

David Dales, BSc (Honours Genetics), Senior Research Technician
Specialty: Molecular and cellular biology and overall laboratory management
Email David Dales

Nicole Hague, BSc, RVT

Specialty: Veterinary technician

Email Nicole Hague

Wendy Kennette, MSc
Specialty: Pathway analysis of metastasis genes
Email: Wendy Kennette

Carl Postenka, BSc, M.L.T., Histology Research Technician
Specialty: Animal handling and all aspects of histology
Email Carl Postenka

Carmen Simedrea
Project: Brain metastasis of breast cancer
Email Carmen Simedrea