Tumor Microvasculature and Microenvironment: Novel Insights Through Intravital Imaging in Pre-Clinical Models

Abstract

Intravital imaging techniques have provided unprecedented insight into tumor microcirculation and microenvironment. For example, these techniques allowed quantitative evaluations of tumor blood vasculature to uncover its abnormal organization, structure and function (e.g., hyperpermeability, heterogeneous and compromised blood flow). Similarly, imaging of functional lymphatics has documented their absence inside tumors. These abnormalities result in elevated interstitial fluid pressure and hinder the delivery of therapeutic agents to tumors. In addition, they induce a hostile microenvironment characterized by hypoxia and acidosis, as documented by intravital imaging. The abnormal microenvironment further lowers the effectiveness of anti-tumor treatments such as radiation therapy and chemotherapy. In addition to these mechanistic insights, intravital imaging may also offer new opportunities to improve therapy. For example, tumor angiogenesis results in immature, dysfunctional vessels-primarily caused by an imbalance in production of pro-and anti-angiogenic factors by the tumors. Restoring the balance of pro-and anti-angiogenic signaling in tumors can "normalize" tumor vasculature and thus, improve its function, as demonstrated by intravital imaging studies in preclinical models and in cancer patients. Administration of cytotoxic therapy during periods of vascular normalization has the potential to enhance treatment efficacy.

Interaction of tumor cells and lymphatic vessels in cancer progression

“…20,90 A high interstitial pressure within tumors may cause intratumoral vessels to collapse to a non-functional state. 91 Thus, the lymphatic vessels observed inside a tumor, are not necessarily functional with regard to fluid drainage or transport of tumor cells, at least in some experimental models. In support of this interpretation, although intratumoral lymphatic vessels were found more frequently in patients with lymph node metastasis than nodal metastasis-negative patients, the extent of peritumoral lymphangiogenesis was concluded to be the most important prognostic factor for the metastasis of melanoma.…”

Autophagy, Stress, and Cancer Metabolism: What Doesn't Kill You Makes You Stronger

“…The nutritionally hungry state of cancers in vivo can arise due to (1) increased need for ATP and anabolic substrates for biosynthetic processes and (2) inaccessibility to nutrients due to abnormal organization and structure in tumor vasculature, resulting in decreased blood flow (Jain 1988), and focal leaks that compromise the blood perfusion in tumors (Fukumura et al 2010). This heterogeneity in vasculature creates hypoxic regions that are refractory to chemotherapy and insensitive to radiation (Fukumura et al 2010).…”

Image-based modelling of skeletal muscle oxygenation

“…Other researchers combined different imaging systems, such as optical coherence tomography (OCT) and fluorescence and hyperspectral imaging [157] and two-photon microscopy combined with a PO 2 nanoprobe [157]. Both OCT and two-photon (or multi-photon) laser scanning microscopy have been used extensively by the group of Jain for the characterization of tumour vasculature, but are both limited to imaging only a superficial fraction of tissue within a small field of view [3,158,159]. These methods are however well established and could-with addition of an oxygenation-sensing technique such as a PO 2 probe-be used to validate results of image-based modelling of muscle oxygenation as images of the vasculature could be cross-correlated.…”