This study highlights the complex role of the tumour matrix as a drug delivery barrier. Although the distribution of larger drugs such as nanomedicines is hindered by steric interactions with collagen, the matrix does not directly limit the distribution of smaller, conventional chemotherapeutics40
. Rather, the matrix indirectly limits the delivery of conventional chemotherapy through vascular compression. Both hyaluronan and collagen fibres contribute to solid stress in tumours: hyaluronan does so by resisting compression, whereas collagen does so by resisting tension and confining the local microenvironment5
. Our results lead to a new model for how hyaluronan and collagen affect vessel compression. As cancer and stromal cells proliferate, they attempt to expand their local tumour microenvironment, exerting tensile stress. This tensile stress stretches collagen fibres in the microenvironment, which store tensile elastic ‘strain’ energy and stiffen, thereby resisting this expansion. The effect is to confine these cells such that the force they generate while proliferating becomes a compressive stress. These cells cannot transmit compressive stress perpendicularly to the fibres of this stiffened collagen; hence, this compressive stress is instead exerted largely on hyaluronan in the local tumour microenvironment. Hyaluronan, whose internal charges repel each other electrostatically and trap water molecules, resists this compression, only storing compressive ‘strain’ energy until maximally compressed. Beyond this maximal compression, the excess compressive stress is transmitted by hyaluronan to tumour vessels. These tumour vessels, which lack the complete coverage by pericytes and basement membrane that fortifies mature vessels, are structurally weak and cannot resist compression. If collagen levels are low in a tumour, the microenvironment is more easily expanded by proliferating cells and thus compressive stress is not produced to as high a level. As a result, hyaluronan does not contribute to vessel compression in collagen-poor tumours. If hyaluronan levels are low, the compressive stress is not transmitted to vessels to as great a degree. Thus, hyaluronan seems responsible for transmitting compressive stress to vessels in all cases when there is no direct cell contact, whereas collagen enables compressive stress to be applied to hyaluronan by cells.
Analyses of retrospective clinical data suggest that the use of AT1 blockers (ARBs) and ACE-Is to manage hypertension in cancer patients receiving standard therapies is correlated with longer survival in pancreatic and other cancers41
, as well as a reduced risk of recurrence in breast cancer44
. However, a causal relationship between the use of ARBs/ACE-Is and its clinical benefit—as well as the mechanism behind this potential effect—has not been revealed. AT1 signalling has been shown to increase VEGF expression by CAFs45
, and both ACE-Is and ARBs can decrease VEGF expression and angiogenesis46
. It has therefore been assumed that their indirect antiangiogenic properties, through downstream VEGF inhibition, benefit survival additively. Our current findings, in line with our previous report14
, do not support this antiangiogenic mechanism. Further, we detected no growth delay or survival benefit with losartan monotherapy in our study. This is in contrast to the ability of angiotensin signalling through AT1 to promote tumour growth and metastasis32
, with signalling through AT2 hindering growth50
. This is perhaps because these growth inhibitory effects are primarily seen at much higher doses of ARBs36
or with long-term treatment52
; indeed, when used at low doses, ARBs have been shown by others to not cause a growth delay47
. It is also possible that this VEGF inhibition is because of direct effects of angiotensin inhibitors on cancer cells, and that our models do not respond similarly because the cancer cells used do not express high levels of AT1 or AT2. These inconsistent data notwithstanding, it should be noted that antiangiogenic therapy with bevacizumab has failed to prolong survival in desmoplastic tumours such as breast and pancreatic cancer3
, casting doubt on a possible antiangiogenic mechanism for the benefits observed with angiotensin inhibitors.
Here we have found that angiotensin inhibitors actually increase vessel perfusion through vascular decompression, doing so by reducing stromal activity and production of matrix components responsible for compression. Notably, these drugs are the first to target all stromal components (CAFs, hyaluronan and collagen) known to contribute to solid stress5
. Our findings also suggest that AT2 agonists or inhibitors of downstream signalling through TGF-β1, CCN2 or ET-1 may similarly reduce solid stress to enhance chemotherapy, although such agents have not been tested in this way. Similarly, angiotensin (1–7), a MAS agonist that can reduce CAF matrix production, may be useful for targeting solid stress53
. Meanwhile, there are challenges to address for translation. Deleterious effects on blood pressure may contraindicate angiotensin inhibitors for some patients14
. Further, we expect that angiotensin inhibitor distribution into tumours may be the most important factor controlling efficacy: drugs displaying a lack of tissue penetration (such as candesartan) would therefore be poor candidates relative to those with high penetration (such as losartan and telmisartan)55
. Indeed, the inadequate tumour penetration of candesartan may explain why it only improved chemotherapy outcomes modestly, when comparing high versus low candesartan doses, in a recent pancreatic cancer study54
. These factors are why losartan was selected over other angiotensin inhibitors for a recently initiated clinical trial in pancreatic cancer (NCT01821729) at Massachusetts General Hospital. Regardless, the safety and low cost of ARBs and ACE-Is—along with their potentiation of conventional chemotherapy—make a strong case for repurposing angiotensin inhibitors as adjuncts for cancer therapies.