Spatial heterogeneity of oxygenation and haemodynamics in breast cancer resolved in vivo by conical multispectral optoacoustic mesoscopy

Abstract

The characteristics of tumour development and metastasis relate not only to genomic heterogeneity but also to spatial heterogeneity, associated with variations in the intratumoural arrangement of cell populations, vascular morphology and oxygen and nutrient supply. While optical (photonic) microscopy is commonly employed to visualize the tumour microenvironment, it assesses only a few hundred cubic microns of tissue. Therefore, it is not suitable for investigating biological processes at the level of the entire tumour, which can be at least four orders of magnitude larger. In this study, we aimed to extend optical visualization and resolve spatial heterogeneity throughout the entire tumour volume. We developed an optoacoustic (photoacoustic) mesoscope adapted to solid tumour imaging and, in a pilot study, offer the first insights into cancer optical contrast heterogeneity in vivo at an unprecedented resolution of <50 μm throughout the entire tumour mass. Using spectral methods, we resolve unknown patterns of oxygenation, vasculature and perfusion in three types of breast cancer and showcase different levels of structural and functional organization. To our knowledge, these results are the most detailed insights of optical signatures reported throughout entire tumours in vivo, and they position optoacoustic mesoscopy as a unique investigational tool linking microscopic and macroscopic observations.

Photoacoustic imaging biomarkers for monitoring biophysical changes during nanobubble-mediated radiation treatment

“…Similarly, TUNEL is commonly used to quantify cell death within tumors exposed to various cancer treatments [ [51] , [52] , [53] ]. Along with H&E, these histological markers have been used successfully used to study the morphology of the tumor vasculature and cancer cells in studies involving PA imaging [ [54] , [55] , [56] ]. The H&E, TUNEL and CD31 sections were sequentially acquired within 10 μm of each other.…”

Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling

“…From the above mentioned standpoint, the traditional anti-angiogenesis can deeply affect anti-tumour immunity, as full doses of drugs shrink the tumor, leading to cancer hypoxia and priming immune suppressive cells’ infiltration [ 160 ]. A wise use of therapeutic strategies halting the cancer angiogenesis must thus take into account the abnormal metabolic microenvironment characterizing a heterogeneous oxygenation [ 161 , 162 ]. Assessing oxygenation in the different layers of tumour pinpoint that there is a progressive increase of nutrient and oxygen levels across the inner depth [ 162 ], thus fueling genomic instability [ 163 ], the cancer progression (PD) [ 16 ], the switch to anaerobic metabolism [ 164 ], as well as the epithelial–mesenchymal transition, metastases [ 165 ], and the induction of cancer “stem cell” phenotype [ 166 ].…”

“…A wise use of therapeutic strategies halting the cancer angiogenesis must thus take into account the abnormal metabolic microenvironment characterizing a heterogeneous oxygenation [ 161 , 162 ]. Assessing oxygenation in the different layers of tumour pinpoint that there is a progressive increase of nutrient and oxygen levels across the inner depth [ 162 ], thus fueling genomic instability [ 163 ], the cancer progression (PD) [ 16 ], the switch to anaerobic metabolism [ 164 ], as well as the epithelial–mesenchymal transition, metastases [ 165 ], and the induction of cancer “stem cell” phenotype [ 166 ]. Hypoxia is a hallmark of cancer, inducing many abnormalities with prognostic consequences linked to defects in apoptosis and autophagy [ 167 , 168 ] and the resistance to radio-chemotherapy [ 169 , 170 , 171 ] and immunotherapy [ 13 , 172 , 173 ] likewise hamper the cancer aggressive phenotype acquisition, while shaping a pro-angiogenic, inflamed, and immunosuppressive neoplastic ecosystem [ 154 , 174 , 175 ].…”

A Review of Endogenous and Exogenous Contrast Agents Used in Photoacoustic Tomography with Different Sensing Configurations

“…Imaging hemoglobin with PAT can help to visualize the development of new vasculatures such as angiogenesis, which is a crucial parameter for early detection of tumor development [ 10 ]. Multiple studies had demonstrated the ability of PAT in early-stage cancer detection by monitoring the change in vasculature density [ 11 , 12 , 13 ]. Lin et al has demonstrated the use of a PACT system in detecting human breast tumor with a penetration depth of 4 cm within a single breath-hold [ 14 ].…”