YSN-ASM Column: Blood vessels – the lifeline of the big ‘C’
by Dr. Oon Chern Ein
Past visiting hours, an eerie silence echoed my footsteps along the hospital hallway. In each room, lay somebody else’s loved ones – a handful of them still laced with faith and optimism, while others cried silently having lost the will to live. The bedsides at the palliative care unit were festooned with flowers and hopeful get-well-soon messages as lady death awaited. Back at the outpatient unit, the nurses called out the names of the seemingly frail and weak. Having gone through rounds of chemotherapy, the fight to survive continued as the drugs wiped out their immune systems. Tears welled up. I knew that some of them would recover, however, some names would never be heard of again but to be laid to rest… forever. In another room, industrious workers in white lab coats were seen preparing samples to be screened and tested for markers of the disease. Blood samples, stool samples, biopsies and unrecognisable organs among others- I wondered how an organ could look so gory and balloon to double or triple its size!? A strong desire grew from within me- a desire to understand this malignancy and to find a way to treat it. Fast forward ten years, I find myself fulfilling my aspiration as a molecular oncologist, battling this disease through research to bring findings from bench to clinics.
This deadly disease is none other than cancer, feared by people however not fully understood by many. We are at constant war against cancer. Cancer is not merely caused by the uncontrolled growth of cells to form a tumour mass, but also due to the failure of machinery to regulate their own growth. In the 1970s, Judah Folkman championed the idea that tumour growth is dependent on functional blood vessels, a process known as angiogenesis which describes the growth of new vessels from pre-existing vessels. His approach has generated controversies as have many other important scientific discoveries, due to contradiction to the popular beliefs at that time . Today, angiogenesis is accepted as one of the hallmarks of cancer that is vital in tumour progression and spread of cancer (metastasis). Tumour size beyond 1-2 mm3 requires blood vessels to supply oxygen and nutrients for growth. Ironically as a tumour grows, the rapidly dividing cancer cells outgrow its blood supply, leaving the inner core deprived of oxygen supply (hypoxic) – a condition known to stimulate angiogenesis. When the blood supplies are disrupted, tumours may starve and eventually die (Figure 1). Hence, targeting tumour vessels could be an effective therapeutic strategy, especially for patients who acquire resistance to chemotherapies. Moreover, some patients may show resilience to current anti-angiogenic drugs, thus the need to uncover novel vessel modulating agents to be used alone or as adjuncts to conventional therapies in the treatment of cancer. In this regard, our group uses synthetic compounds or blocking antibodies to block particular signalling pathways which are involved in mediating the formation of blood vessels in tumours and has already identified promising leads.
Evolving scientific discoveries have uncovered yet another layer of complexity which challenged the dogma postulating that inhibiting angiogenesis could inhibit tumour growth, as the functionality of the vessels heavily determines the therapeutic outcome [2,3]. On one hand, blood vessels are needed to deliver chemotherapy drugs more efficiently to the tumours. However blood vessels in tumours are usually irregular and fragile, therefore affecting the optimal delivery of chemotherapy that results in poorer efficacy. These leaky vessels also allow cancer cells to break through the vessel barrier, hijack the blood transportation system and spread to distant organs (metastasize). In contrast, treatments that obliterate tumour vasculatures have not always been successful. In some instances, patients even develop resistance to these drugs, resulting in metastasis or relapse of the disease. So what is the verdict? How should novel therapies be designed to deliver the best therapeutic outcome? Recent discoveries have reported that correcting the structure and function of tumour vessels may aid chemotherapy delivery to achieve a better outcome , especially in conjunction with immunotherapy to enhance the body’s natural defences. This is based on the postulation that repairing the impaired blood vessels could increase the consistency of blood flow within different regions of the tumour, thus reducing the incidence of oxygen deficiency and preventing the formation of leaky vessels. The fortified blood vessels may then reduce the ability of cancer cells to break through the vessel wall, enter the bloodstream and metastasize to other parts of the body .
Altogether, these have prodded scientists to revisit some of the basic concerns involved in tumour angiogenesis for optimal treatment outcome. Owing to the complexity of the cellular environment, scientists are still trying to understand the relationship between blood vessels and cancer in the bid to manipulate the vessels to shrink tumours. As of now, the standard US Food and Drug Administration approved drugs used in the clinics that function by suppressing blood vessel formation in cancer. These drugs block specific molecules or receptors in the cells that are responsible for triggering the signals for vessel growth in tumours. They include axitinib, bevacizumab, ziv-aflibercept and sorafenib for the treatment of highly vascularised tumours including renal cancer (Figure 2), bowel cancer, lung cancer, breast cancer and liver cancer (data from http://www.cancerresearchuk.org).
 Zetter BR. The scientific contributions of M. Judah Folkman to cancer research. Nat Rev Cancer. 2008; 8: 647-54.
 Li JL, Sainson RC, Oon CE, et al. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 2011; 71: 6073-83.
 Oon, C.E., Bridges, E.M., Sheldon, H., Sainson, R.C. A., Jubb, A., Turley, H., Leek, R., Buffa, F., Li, J.L., Harris, A.L. Role of Delta-like 4 in response to Jagged1-induced tumour angiogenesis and tumour growth (In press, Oncotarget)
 Cantelmo AR, Pircher A, Kalucka J, Carmeliet P. Vessel pruning or healing: endothelial metabolism as a novel target? Expert Opin Ther Targets. 2017: 1-9.
 Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011; 91: 1071-121.
About the Author
Dr Oon Chern Ein pursued her BSc (1st Class Hons) in Biotechnology at Universiti Kebangsaan Malaysia before securing a scholarship from the Ministry of Higher Education Malaysia to further her doctorate studies in Medical Oncology in University of Oxford, United Kingdom. She then trained at Karolinska Institutet, Sweden as a postdoctoral fellow before returning to Malaysia to serve as a lecturer at Institute for Research in Molecular Medicine, Universiti Sains Malaysia. Her area of research includes exploring the benefits of novel synthetic compounds towards the development of novel molecular targeted therapy in cancer.
Dr Oon is also heading the Universiti Sains Malaysia Industry and Community Network initiative working closely with MAKNA National Cancer Council Malaysia to disseminate knowledge on cancer to cancer survivors and the public through talks, home visits and motivational workshops. Dr Oon would like to acknowledge Union for International Cancer Control ICRETT Fellowship, L’Oréal-UNESCO for Women in Science and MAKNA Cancer Research Award for financial support. More information about the author can be found here.