VEGF inhibitors may accelerate tumour invasion

Holy cats! I just read a rather unsettling Science Daily article (see: A new study shows that angiogenesis-inhibiting drugs may turn a blissful “well-fed” cancer into an angry aggressive type.


A group of U.S. and Spanish researchers found that mice first infected with pancreatic cancer and glioblastoma and then treated with the anti-angiogenic drug sunitinib responded rather well in the beginning…but, after a few weeks, there was an adaptive response by the tumor. The glioblastomas increased invasion into adjacent normal tissue. The pancreatic tumors also became more invasive and, in addition, metastasized to the liver.


This study suggests that tumours have a remarkable ability to develop survival strategies. If their blood supply is cut off, they will find other ways to feed themselves and survive…apparently, by spreading and becoming more dangerous. A scary thought indeed.

This article led me to reflect, once again, on the use of aggressive treatments versus gentler, less invasive ones…


  1. I think we sort of knew this. Cells are pretty complex. Signaling pathways contain branching, cross-talk feedback and feedforward mechanisms that help the cell to adjust to different conditions.

    When you have a tumor that’s growing and it’s relying on, say, VEGF as a growth factor to help develop the tumor environment, inhibiting VEGF will make the tumor environment very hypoxic. This will cause other proteins to be synthesized and will help the cells survive in other ways.

    The reality is, I think, that it isn’t just about high versus low dose, it comes down to combination therapies. If there are five routes to get from point A to point B you won’t stop someone determined to make the trip by blocking one route. In this case you need to inhibit multiple pathways to get the desired effect.

    There’s a whole other set of arguments to be made for high versus low dose medications but we are seeing more and more trials of combination therapies. Unfortunately this gets very complex as things that just “should work” don’t always. A combination trial using Avastin and rbitux (I think) was recently stopped because the combination made the disease worse, not better. Nobody expected that.

    I think of cancer as a sort of rubick’s cube. You can spend all your energy and focus solving one side but unless you have a system you will do so at the expense of messing everything else up. We just don’t have a coherent method for solving such a complex system at this point.


  2. Hi Chris,

    In fact, as we can read in the article, these researchers “call for preclinical and clinical trials combining angiogenesis-inhibiting drugs with ones targeting the capability for invasion and metastasis.” Combination therapies, exactly.

    I just wish that research would also focus on, test and make more bioavailable (it wouldn’t take much), non-toxic substances such as curcumin, which inhibits an amazing number of tumour survival pathways. It does precisely what you suggest…attacking cancer on different fronts. And this activity can perhaps be potentiated in combination with other substances…PTL, e.g.

    But no, the overwhelming majority of substances that get tested and pushed into clinical trials are the potential money-makers that frequently have a million negative side effects…it’s frustrating. At least for me.

    And so I continue to take curcumin (and whatever else I decide to test) in various forms, in an attempt to find a non-toxic combination that works for me…that can keep me stable for as long as possible…

  3. For a drug company it really makes no sense to work on a substance that doesn’t affort them patent protection and, hence, profit potential. It doesn’t make them evil, it just makes them busineses. In fact they spend a fair amount of time starting with a substance they can’t patent and creating analogs that they can patent which may or may not have the same effects.

    Researchers often have the goal of publsihing their research. Very often they don’t have any expectation or perhaps even interest in pusuing the research into the clinic. As a result it’s often OK for them to do research with a substance – like curcumin – that doesn’t readily translate into something you can replicate. It isn’t part of their research.

    What I beleive is needed is more governance from the organizations like NIH that fund a lot of research. They don’t seem terribly goal oriented. They pursue “interesting” research without considering whether it ultimately accrues toward a goal. I do support some pure research that isn’t governed by a set of goals; discovery is sometimes a very random thing. But, to your point, it would be great to have research and trials focused on making curcumin of more benefit.


  4. One of my issues is that few dollars are spent on prevention of cancer.

    There is much talk about getting screenings for detection. The earlier the better. Well of course IF one has cancer the earlier one detects it the better that is. But detection is NOT prevention…..and early detection is also not necessarily a “cure” particularly for cancers that are aggressive. Plus some cancers come about silently without any signs or any means to screen for them. It’s just suddenly Wham Bam.- suddenly one has cancer and sometimes when it is learned the cancer is everywhere.

    About 3-4 years back I learned that only about 5% of research dollars go into prevention. I agree that where there are big bucks to be made and that is where the “work” is going to be done. I read in a best selling book about cancer that even if it took a billion dollars to come up with a cancer treatment, the drug company will spend a billion dollars because they stand to make BILLIONS($$$$$) if their drug works.

    Yet within foods – where there are many phytochemical that could very well cure cancer if money was put into human studies or prevent cancer….well as the author ( a cancer patient himself and an MD) of that best selling cancer book that I read says – “they” can’t patent a raspberry.

    Where Hippocrates said- “Above all do no harm”…..

    ……he also said, “Let thy food be thy medicine and thy medicine be thy food”.

    I don’t know- am I cynical to ask the question- Has cancer become an industry???

  5. p.s.
    Just to clarify I am certainly not against drugs that can cure. I know people whose lives have been saved and thank goodness.

    Just saying I wish more money/ science/ thinking/ consideration was put into prevention which would include looking at other means besides detection. And then if cancer was detected- well…..I guess I trailed off about drugs….and the $$$$ to be made.

  6. I agree with Chris that we are dealing with to complex system. According to new biology we have 50 – 70 trillion cells. We even do not know more precisely how many. The function of the cell is regulated by epigenetic as well as genetics. This information is even not included in medical students’ curriculum. Each cell as any machines has parts. Parts in living organisms are build from proteins. We have 200 000 different proteins in each cell. Let’s assume that we already know 100 different processes in myeloma. We are short of knowing 199 900. One cell may have approximately 900 different receptors. Modifying receptors with few substances like drugs or curcumin my change natural history and prolongs live but will never bring permanent solutions like cure. Myeloma stem cell was discovered in just 2003 by John Hopkins University team, although its existence was predicted at least 30 years earlier. Current medications do not kill myeloma stem cells without killing the host. The answer is nutrition. Provide appropriate building blocks of not thermally change proteins and all other nutrients and we may have a chance. Clean the microenvironment of bone marrow, correct Ph, remove toxins particularly in a place of mutated myeloma stem cells which are probably the effect of candida fungus infection according to oncologist Dr Tullino Simoncini… I have some positive effect from no drug, nor supplement approach. My blood results normalize, B2 microglobuline is just 1.9, M-spike 0.8, serum ? light chain 6.82, Serum ? 27.6, and symptoms disappears without any drugs or supplements. In a past, when I was desperate, I took many different supplements including curcumin. Total cumulative dose was about 1.5 kg. I try small, medium and high doses in different combinations. I try curcumin with many different solvents, but I did not notice any positive results. I went through high dose dexamethasone thalidomide therapy and M-Spike went from 6.3 to 0.7 then to 1.0 before transplant. Autologus stem cell transplant with high 200 mg/m² mephalan did not change much. 5 months after transplant M – Spike was 1.3. I will be more vocal after I go and stay in complete response…
    Peter 06

  7. Hi, I was diagnosed with MGuS age 39 in 8/2010 after an spep revealed small M spike. Flash forward to first follow-up summer 2013 and BMB revealing 5% BMPC, M spike rose from .100 g/dL to .400. Then April 2014 BMB at .major cancer center revealed 10% BMPC with aberrant % of 91% including CD56, 117 positive and lacking other antigens found on normal PCs. Also small mature cd20+ plasma cell morphology noted and m spike now. 700. Based on BMPC % I’m now barely Smoldering Myeloma classified though for some reason the hematologist and entire lymphoma Myeloma dept often refers to me as MGUS .
    I also have immunoparesis as my IgG kappa situation results in IgM below normal for the past six months . IgM was near low normal since first tested and lower each time until under 35 mg/dl the lower limit of normal per my lab’s range. Also a positive Bence Jones Proteinuria was found IgG kappa via Immunofixation urine while UPEP has been clear of BJP meaning BJP present but not at a high enough level for UPEP to quantify the measurement of BJP. 24 hr urine always results in approx 200 mg of protein which is abnormally high but apparently not high enough to worry the doctors.
    My reason for posting here was to ask about VEGF. Besides an Amyloidosis fat pad biopsy recently January 2015 a VEGF level was tested to rule out POEMS. Pretty major lower leg edema began Sept 2014 which promoted VEGF , amyloid , testing as well was BNP cardiac indicator which was slightly high.
    While VEGF was sent to Mayo then to a lab in California (lab corp research facility) the level wasn’t high which was a relief but the level also want normal. VEGF was BELOW normal with a value do under 30, exact value not given.

    Does anyone know what an abnormally low VEGF level may represent especially taking into consideration Smoldering Myeloma / MGUS? I’m glad VEGF wasn’t high but while there’s little out there tied to know VEGF levels it seems low levels of an angiogenesis are associated with CAD and other cardiac issues as well as possibly neurological issues including ALS. Anyone know possible implications of low VEGF?

    Thanks for the informative blog and piccolo is the neatest cat.

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