Improving Cancer Care by Studying Tumor Vessel Formation

John Haaga, MD, FSIR, is a tenured professor and emeritus chairman of the Department of Radiology at Case Western Reserve University School of Medicine and University Hospitals Case Medical Center. He was invited to the 2015 Society of Interventional Radiology Annual Scientific Meeting to discuss tumor blood vessel formation to enhance and improve the care that interventional radiologists are providing in an interventional oncology setting. Interventional Oncology 360 asked Dr. Haaga to share some details from his presentation.

Q: Please describe the topic of your talk here at the SIR meeting.

A: What we’ve been working on is a new approach to vessel formation and potentially a new treatment. In regard to cancer blood vessels, we’ve always been taught and told that cancers need oxygen in arteries, so one would logically conclude that you can kill cancers by plugging the arteries. Well, we’ve been doing this for 30 years and still we’re not curing the cancer. This was our impetus to start looking at the basis of some of the traditional beliefs about vessels relative to cancers. 

If you look at the basic metabolism that we’ve talked about, we’ve all been told that cancer prefers aerobic, because it’s efficient: 34 to 38 ATPs. Modern chemistry tells us that glycolysis only produces 2 ATPs and 2 lactates but is 100 times faster, so for every 38 ATPs aerobic makes, cancer can make 200 and cancer’s need for energy is gluttonous. In fact, if you looked at a single mitosis of a cell, it takes and hour and requires about 2 to the 8th ATPs. It needs lots of energy so it’s much faster. This appears that glycolysis is actually more important that we expected. 

Q: How can you explain this?

A: Information in the modern literature can only be appreciated if you take the time to read through hundreds of journals. Most don’t have that time, but as we started to work on this, 10 years ago, we found some really remarkable things. For example, glycolysis not only provides energy, but it provides the absolute essential building products to make new cells. For a cancer cell to divide, the mother cell must double the biomass, double the membranes, double the DNA and so on, and in modern literature, journals like Science show that all these substrates come from the side reactions of glycolysis. If there’s no glycolysis, there’s no growth of the mother cell, there’s no division. 

The other thing we’ve found in very recent times is that lactate is not just a waste product. It actually turns on many pro-cancer processes that we as physicians never realized. For example, most of us had no idea, even now, that cancer cells can move like an amoeba, yet in the cell metabolism literature, it is very well defined, lactate induces a number of molecules that makes the actin in the cancer cell move like an amoeba. If you talk to biochemists, they’ll say they knew that. I ask, “Well, why didn’t you tell us?”  

Q: What other information is helpful for interventional oncology clinicians to know?

A: We know the immune system tries to protect the body from cancer cells, and it turns out if you read the Journal of Immunology, lactate shuts down the immune system locally. It stops natural killer cells, it shuts down T-lymphocytes, it prevents dendritic cells from androgen loading, and it prevents monocytes from transforming to macrophages. In addition to reading this in the literature, I recently had the opportunity to talk to the NIH immunology oncology lab and I asked them what they thought and they said it was absolutely correct. So we as radiologists, as interventionalists, have to really step up to the plate and start looking at new things. 

Einstein said the definition of insanity is doing the same experiment and expecting different results. We found in the literature that there’s a whole different vascular genesis process for glycolysis than aerobic. Aerobic does require arteries, but glycolysis requires drainage vessels. Cancer wants to kill us, so it does not want to shut down glycolysis. If lactate gets too high, you get end-product inhibition. It needs lymphatics and veins to control the levels of lactate. 

Q: How do these vessels form? 

A: It turns out that lactate induces major vascular growth factors, which are VEGF and FGF, and glycolysis with lactate is the main method by which surgical wounds heal. Surgical wounds have to be normoxic, and lactate, released by macrophages, induces these factors we’ve talked about. 

Now the really unusual thing we’ve found, and it’s well documented in high-quality journals, is that lactate induces the vascular factors but the sequence of vessel development is not what we’ve been expecting. It’s actually lymphatics first, then veins, and then arteries. And we won’t quote all the papers, but we’ve seen papers from the Proceedings of the National Academy of Sciences, with Impact Factor 9, that say the lowest concentration in FGF starts lymphangiogenesis first, and then the blood vessels. 

Q: Why hasn’t this information made it to the oncology community? 

A: It’s gotten lost because there’s so much literature and very few people had the time to read all these diverse journals. So based on these data and the new theory, we hope it will be vetted, and it’s either proven right or wrong, but we have actually almost completed a proof study. We’ve paralleled and adapted a paper that appeared in Proceedings of the National Academy of Sciences by Indraccolo et al (2006). Indraccolo used a cell line called MOLT-3 that is a nonangiogenic, nontumorigenic cell line. He showed that if you inject it by itself, it will not grow. If he injected it with FGF or VEGF or super-natant fluid, from Kaposi sarcoma, where the cells have been killed, it will grow. We got his cell line from Italy, we got a new batch of the same cell line, we used both cell lines and when we put them with lactate, the MOLT-3 grows. We believe that we will have a further confirmation that this indeed is a valid hypothesis. 

Q: What does this mean for cancer treatment?

A: It means that we can better understand some of the other things we do in imaging, like CT perfusion, or MR perfusion and that’s been published recently in the American Journal of Radiology, but it also means we need to refocus our treatments. It means every time we treat cancer, we treat aerobic and glycolysis simultaneously. If we do this there’s no ATP, the cells will die and we’re hopeful that we found a new method of shutting down glycolysis through the back door through the cancer’s waste cycles and time is a little too limited to go through all that but basically that would not affect normal cells, it only affects the waste cycle side of the cancer cells. We think this is a new avenue that we as interventionalists have to pursue. 

It’s interesting that somehow we think that radiologists don’t know about angiogenesis, but it turns out the first person to describe VEGF, in 1939 in the American Journal of Radiology, was a radiologist who did an animal experiment, and he concluded by saying “we’re forced to conclude, there’s a humeral substance secreted by cancer cells to stimulate vessel growth.” 

And we’re moving ahead at out own institution, but we’ve trained a number of very bright radiologists who are now practicing and helping to investigate this. One of these is Hooman Yarmohammadi at Sloan Kettering who is starting an IRB soon to help study this new approach to treatment and also we have a bright, young faculty member who’s a faculty member at the University of Virginia, Luke Wilkins, who’s also working in these areas and we would invite anyone who’s interested to contact us. We’d love to collaborate; we really want this to move ahead. 

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Editor’s note: Disclosure: Dr. Haaga has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. He reports no disclosures related to the content herein. 

Suggested citation: Ford J. Improving cancer care by studying tumor vessel formation. Intervent Oncol 360. 2015;3(5):E57-E59.