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 The Microenvironment of Human Tumours
Michael Milosevic, MD, BASc,
FRCPC
Co-Principal Investigator Project 1, with Dr. Hill:
Hypoxia and Interstitial Fluid Pressure in Tumour Progression and Metastases
Co-Principal Investigator Project 5, with Dr. Fyles:
Biomarkers and Imaging Studies of the Tumour Microenvironment: Treatment Response and New Therapeutic Targets in Cervix and Prostate Cancer
There is substantial evidence that the cellular microenvironment exerts profound effects on tumour growth, differentiation, metastasis and response to therapy. Tumours are highly dynamic systems characterized by complex interactions among the vascular, interstitial and cellular compartments. The abnormal vascular architecture in tumours, which arises mainly because of unregulated angiogenesis, contributes to inefficient oxygen delivery and hypoxia. Hypoxia is an important cause of radiation resistance by mediating cellular and DNA damage via free radical formation. Hypoxia is also known to have profound effects on genetic instability, expression of genes related to angiogenesis, invasion and metastasis, and selection of cells that are resistance to apoptosis. Clinical studies have shown that hypoxic primary tumours are associated with more aggressive malignant phenotypes, higher rates of metastatic disease, and higher recurrence rates regardless of whether treatment is with radiation or surgery.
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Model of Tumour
Interstitial Fluid Pressure |
The abnormal tumour vasculature also contributes to elevated interstitial fluid pressure (IFP). High capillary permeability and a lack of functional intra-tumoural lymphatic lead to accumulation of fluid in the interstitium, distention of the elastic interstitial matrix, and elevation of the pressure above normal atmospheric levels. In most case, IFP is equal to the average capillary pressure and variability in IFP among tumours mainly reflects difference in capillary flow resistance. It has been suggested that IFP provides a marker of vascular "normality" in tumours, and has been implicated as an important cause of impaired drug delivery.
The Microenvironment of Cervix Cancer
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Cervix Carcinoma (H&E
Staining) |
We performed oxygen and IFP needle-based measurements in over 100 patients with cervix cancer
prior to treatment with radiotherapy. There was no correlation between oxygen levels and IFP.
Hypoxia was an independent predictor of disease-free survival (DFS) in radiographically
node-negative patients. There was no significant difference between oxic and hypoxic tumours in the risk of
pelvic recurrence, but patients with hypoxic tumours were more likely to develop para-aortic lymph node or
distant metastases. IFP was found to be strongly predictive of DFS for the entire cohort (not only node-negative
patients), independent of clinical prognostic factors and tumour oxygenation. Patients with high IFP were more
likely to develop recurrent tumour in the pelvis, as well as distantly. This study, which is the first to
demonstrate an
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Cervical Cancer Disease-Free
Survival |
important effect of IFP on patient outcome, provides strong evidence that the tumour
microenvironment influences cervix cancer progression and response to treatment. Therefore, therapeutic
strategies that improve oxygenation or reduce IFP, when used in combination with standard radiotherapy and
concurrent chemotherapy, might also improve tumour control and patient survival. Serial measurement of
oxygenation and IFP before and after treatment might provide an early indication of biologic tumour response
to these targeted treatments.
We have also demonstrated the feasibility and potential importance of biologic imaging in cervix cancer.
Approximately 40 patients have now undergone dynamic, contrast-enhanced CT and MR imaging of intrinsic tumour
physiology prior to treatment. We found CT-based estimates of tumour blood flow to correlate with polarographic
oxygen measurements. In addition, vascular permeability from dynamic MRI correlated inversely with IFP
(unpublished). Changes in these physiologic parameters might provide important information about response to
biologically-targeted treatments in advance of clinical or radiographic tumour regression.
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DCE MRI in Cervix Cancer |
Our work to date suggests that treatments targeted at the abnormal tumour vasculature might be beneficial in
patients with cervix cancer, particularly if used in combination with radiotherapy and concurrent cisplatin
chemotherapy. Anti-angiogenic therapy has been shown in laboratory and clinical studies to reduce IFP, improve
oxygenation and reduce capillary permeability, presumably by promoting vascular "normalization" and more
efficient delivery of oxygen and other nutrients. We have demonstrated in a series of laboratory experiments
that the anti-vascular agent ZD6162 causes significant reductions in tumour IFP within 48 hours of administration.
Malignant cells in tumours with high pre-treatment IFP were less likely to be killed by ZD6126 than cells in
tumours with lower pressures. In addition, we recently completed a clinical study of celecoxib in combination
with radiation and cisplatinum in patients with cervix cancer. Celecoxib has been demonstrated to have prominent
anti-angiogeneic properties in pre-clinical models.
Ongoing and planned studies aimed at better understanding the tumour microenvironment and improving the outcome
of patients with cervix cancer include:
1. Hypoxia and IFP in cervix cancer
2. Biologic imaging of cervix and prostate cancer with dynamic CT and MRI
3. Spatio-temporal variability in the structure and function of human tumors4. Inhibition of angiogenesis in
cervix cancer
The Microenvironment of Prostate Cancer
Prostate cancer is the most common malignancy among North American men, and imposes a huge
social and economic burden. Most patients have low or intermediate risk disease at diagnosis that is clinically
confined to the prostate gland. Depending on co morbidities and individual preference, they are candidates for
potentially curative treatment with either radical prostatectomy or radiotherapy. Despite technical advances in
both of these treatments over the past decades, approximately 25% of these patients will develop progressive
disease either locally in the pelvis or at remote sites, most commonly in bone. This underscores the importance
of better understanding the biologic factors that are responsible for malignant progression, the development of
metastases and the failure of currently available treatments, including androgen deprivation.
We have now measured hypoxia in almost 300 patients with clinically localized, intermediate-risk prostate
cancer prior to treatment with high-does conformal or intensity modulated radiotherapy. Our results have
demonstrated that prostate cancer is hypoxic, and that the distribution of oxygen values across patients
is similar to cervix cancer and other human tumors. A preliminary analysis of PSA-progression free survival
suggested that patients with hypoxic tumours are likely to recur than those with oxic tumours. However,
longer patients follow-up is required to confirm this early observation.
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Ultrasound Guided
Prostate pO2 Measurements |
Early prostate cancer is androgen sensitive, and androgen withdrawal is frequently used in combination with
radiotherapy. Several clinical studies have demonstrated improved local tumour control and DFS when androgen
ablation is added to radiotherapy, although the mechanism of this effect remains unknown. Studies of androgen
sensitive tumours in animals have demonstrated early regression of the abnormal tumour vasculature with androgen
ablation, coincident with the appearance of more normal-appearing vessels and improved tumour oxygenation.
Continued hormonal treatment eventually leads to a secondary phase of abnormal angiogenesis, consistent with the
development of hormone-refractory disease in patients. Our preliminary results in patients with prostate cancer
suggest a trend towards higher O2 values in patients who had received previous androgen ablation relative to
those with no prior treatment. This suggests that the beneficial effect of androgen ablation, when used in
combination with radiotherapy, may be at least in part mediated by vascular "normalization" and improved tumour
oxygenation.
Ongoing and planned studies aimed at better understanding the tumour microenvironment and improving the outcome
of patients with prostate cancer include:
1. Hypoxia in prostate cancer
2. BOLD imaging of hypoxia in prostate cancer
3. The effect of androgen ablation on prostate cancer hypoxia
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