Modulation of tumour vascular network to optimize the response to cytotoxic treatments
(2006)
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- In tumour, the blood vessels are immature and present some structural and functional abnormalities. Most of them are dilated, tortuous with extensive fenestrations, branchings, and arteriovenous shunts. The net result is a vascular network that is spatially and temporally heterogeneous, leading to an abnormal tumour microenvironment characterized by a chaotic, highly variable perfusion, hypoxic zones, acidosis, and high interstitial fluid pressure which hinder therapeutic effectiveness. Thus, efforts must be made to counteract those abnormalities and find new strategies for transiently opening the tumour vascular bed in order to alleviate tumour hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents to increase the efficacy of anti-cancer treatments. <BR> Up to now, antiangiogenic treatments were used to suppress tumour vascular supply and then starve tumour from oxygen and nutrients. Nevertheless, experiments reveal that the use of these agents must be seen more as adjuvant agents in combined treatments rather than as a single agent. Recently, the concept of a transient 'normalization' of the tumour vasculature in the early stage of the anti-angiogenic treatment has been proposed: by pruning the immature and inefficient blood vessels with a remodelling of the remaining vasculature, the tumour vasculature could transiently become more "normal". <BR> The first study concerning the non specific anti-angiogenic agent Thalidomide (acting on VEGF and bFGF) supported this process of normalization. Indeed, two days of Thalidomide treatment revealed profound modifications in the vascular supply: a reduction of the number of microvessels with dilations of the remaining ones. As a consequence, a transient increase in tumour oxygenation, paralleling changes in tumour perfusion and interstitial pressure, was reported. The consequences were a better radio- and chemo- therapy efficiency. Other time windows for the combined treatments showed no benefits. <BR> Similarly, another anti-angiogenic agent (SU5416) acting on a specific target (Flk-1 tyrosine kinase activity) was tested. Like Thalidomide, this compound was able to induce a reoxygenation of the tumour after two days of treatment. But surprisingly, it was associated with an inhibition of mitochondrial respiration with no modification on tumour blood flow. The tumour vasculature normalization did not occur in this case. Consistently with these findings, only the radiotherapy was potentiated when combined with SU5416, and not chemotherapy. This is the first time that a long-term inhibition of oxygen consumption is reported. It constitutes a potential novel use for this class of compounds. The use of another specific anti-angiogenic agent similar to SU5416, the ZD6474 compound confirmed those results. <BR> Those experiments showed the complexity of the evolution of tumour hemodynamics after anti-angiogenic treatment. <BR> In a completely different way, a transient opening of the tumour vascular network was performed by directly acting on tumour vessels as a result of an intratumoral injection of botulinum neurotoxin A. Indeed, the results showed that this neurotoxin could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumour vessels. The consequences were the enhancement of tumour perfusion and oxygenation three days after the single intratumoral injection. At this time, both the radio- and chemo- therapy efficiencies were improved. <BR> In conclusion, those four studies demonstrate the need to take into account the evolution of the tumour micro-environment parameters and the different involved mechanisms to define which co-treatment can be helpful and when to apply this co-treatment
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Ansiaux, R. (2006). Modulation of tumour vascular network to optimize the response to cytotoxic treatments. https://hdl.handle.net/2078.5/112185