New Microscopic Technique to Visualise Tumour Blood Vessels

Cancer is the leading cause of death worldwide with close to one in six people suffering from it. Cancer progression causes a lot of changes in the physiology of the system. Apart from this, cancer is not just a tumor but a micro-environment of its own.

Tumor micro-environment majorly consists of tumor cells, secreted factors, extracellular matrix along with the resident host cells. Surprisingly, this micro-environment is an ever evolving entity aiding the progression of the disease. The same micro-environment is also houses the immune cells which fight against the disease. As the tumor progresses there are visible structural changes in the micro-environment. To facilitate this, tumors engage in angiogenesis or the process of forming new blood vessels. Knowing that angiogenesis is inevitable for tumor growth research was carried out targeting this process.

Till date, there are around 10 drugs developed against angiogenesis called anti-angiotensins (AA). They majorly target the Vascular endothelial growth factor (VEGF) and its receptors, the angiotensin receptor blockers (ART). These targets unfortunately have shown to relieve the conditions only for the initial few weeks or in some cases, become resistant to treatment after the first dose. This is because the tumour growth suppresses immune signalling and causes acidosis. Sometimes, hypoxia in the micro environment causes the blood vessels to collapse. Due to these conditions, AA drugs have been found to be inefficient.

Research shows that anti-angiotensins and Angiotensin receptor blockers function better under normoxic conditions as they aid in chemotherapy or radiotherapy. AA drugs, transiently, normalises the tumor micro-environment by improving blood vasculature and alleviating hypoxia. This is called the normalisation window. It has been seen that transient vascular normalisation increases blood flow, immune cell infiltration and oxygen levels. Pre-clinical and clinical studies showed that radiotherapy had better outcomes when applied during vascular normalisation.

A drawback of this system was that extensive use of the AA decreased the normalization window and increased pruning of the blood vessels. Higher doses can starve the tumor of oxygen which leads to reprogramming of the micro-environment and in worst cases, be toxic and fatal for the patients. Secondly, it is difficult to identify the correct normalisation window for different types of tumor. Solid tumors are easy to identify whereas metastasized tumors cause different sets of complications.

To overcome this problem, doctors from Massachusetts General Hospital developed a non-invasive technique to help identify the normalization window and hence, determine the required dose of AA drugs using Multi photon based Phosphorescence quenching microscopy. In this study, they developed a low molecular weight palladium porphyrin probe that could be distributed throughout the tumor and via multi photon microscopy, the tissues can be easily visualized. They called this the multi photon phosphorescence quenching microscopy (MP-PQM).

Using an ART drug, Losartan and MP-PQM, doctors were able to visualize the increased oxygen in breast cancers in both mice and humans. With this approach, doctors can dynamically modulate the nature of the tumor and the heterogeneity of the blood vessels due to tumor formation. Tumour lesions are very heterogeneous in nature. These lesions not only differ from patient to patient but also in the same patient. This indicates the specificity involved in the treating different types of cancers.

In the study, two different murine cancer cells behaved differently when treated with losartan indicating that the usage of drug is spatially different. With the use of MP-PQM, the cancerous tissues can be visualized better, thus aiding cancer treatment.

Using the improved microscopic technique MP-QPM, doctors can treat solid tumors with greater specificity and specializing drug requirements based on the patients tumor.

Author

 Aishwarya Segu is a PhD student from IISER Trivandrum who is fascinated with the working of the brain. She is a curious scientist, an avid reader and a trying writer.