The microenvironment of solid tumours matters

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By Aravind Arepally

Despite the rapid growth of imaging and treatment options in interventional oncology, one area that has been poorly understood and overlooked by the interventional community is the role of the tumour microenvironment and its impact on the delivery of therapeutic agents.

The microenvironment of solid tumours is now well studied and more importantly has been shown to be a significant burden to the delivery of anti-cancer agents into tumour cells. Although the peritumoural stromal architecture seems markedly disorganised, there emerges a consistent configuration across solid tumours. This environment has been generally described as having poorly organised vasculature, a low pH, being hypoxic and elevated interstitial fluid pressures. Of all these features, elevated tumour interstitial pressure has gained interest from both a pharmacological and mechanical perspective as a common dominant feature of tumour biology and thus may have implications for targeted delivery of therapeutics.

Origins of tumour interstitial pressure

The origin of tumour interstitial pressure is multifactorial. Elevated tumour pressure arises from the abnormal permeability of tumour vasculature resulting in the leakage of fluids into the extracellular matrix.  In addition the lack of normal lymphatic drainage along with the mechanical pressure of proliferating cells in a confined space heightens this process resulting in elevation of the pressure1,2. Subsequently, elevation of tumour interstitial pressure releases  peritumoral angiogenic features into the adjacent tissues resulting in angiogenesis and thus further aggravating this process3.

The movement of intravascular drugs and therapeutic agents is a multistep process. Initially, the agent has to reach the tumour via the vasculature, cross the vessel wall through the process of convection and finally, diffuse through the interstitial space to reach the target cells. Throughout this activity, the convection process across the vessel wall is highly dependent upon pressure gradients, whereas the diffusion process is dependent on the density of the stromal matrix1-3. Thus, the presence of elevated pressures impedes the convection process resulting in a markedly heterogeneous intratumoural distribution of therapeutic agents, which can result in reduced efficacy of drugs and radiotherapy1.  

Strategies to overcome tumour interstitial pressure

Several strategies have emerged to modulate or overcome the elevated tumour interstitial pressure. Pharmaceutical approaches lower the tumour interstitial pressure through the use of vascular targeting agents such as vascular endothelial growth factor (VEGF) inhibitors that remodel or “normalise” the vascular flow to the tumour. The direct effect of this technique is to lower the tumour interstitial pressure, restore normal pressure gradients across the vessel wall and thus increase convection transport of therapeutic agents into the tumour. Thus anti-VEGF inhibitors such as bevacizumab and sorafenib have been shown to significantly reduce tumour interstitial pressure4,5. Further, the combination of anti-angiogenic drug with a cytotoxic agent has been shown to have improved therapeutic efficacy. Other physical methods such as irradiation, hyperthermia, hypothermia and photodynamic therapies have also been shown to reduce tumour interstitial pressure by mechanical processes such as cavitation and/or thermal effects on vascular permeability. Finally, transvascular approaches such as elevating the systemic mean arterial pressure or the use of devices (such as balloons and anti-reflux systems) have begun to be utilised to overcome the interstitial pressures to further drive the therapeutic agent into the solid tumours6,7,8.

Conclusion

Transvascular delivery of embolic agents has a unique opportunity to further improve from its current paradigm. As we further understand the interplay between the delivery of targeted therapeutics and its impact on tumour interstitial pressures, new device strategies should arise to broaden our approach to the treatment of solid tumours and provide an opportunity to significantly improve the outcomes of patients.

References

1 Ariffin AB, Forde PF, Jahangeer S, Soden DM, Hinchion J. Releasing pressure in tumors: what do we know so far and where do we go from here? A review. Cancer Research. 2014; 74(10):2655–62.

2 Sheth RA, Hesketh R, Kong DS, Wicky S, Oklu R. Barriers to drug delivery in interventional oncology. Journal of Vascular and Interventional Radiology: JVIR. 2013; 24(8):1201–7.

3 Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nature reviews. Clinical Oncology. 2010; 7(11):653–64.

4 Raut CP, Boucher Y, Duda DG, et al. Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948). PloS One. 2012; 7(2):e26331.

5 Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Research. 2004; 64(11):3731–6.

6 Irie T, Kuramochi M, Takahashi N. Dense accumulation of lipiodol emulsion in hepatocellular carcinoma nodule during selective balloon-occluded transarterial chemoembolization: measurement of balloon-occluded arterial stump pressure. Cardiovascular and Interventional Radiology. 2013; 36(3):706–13.

7 Nagamitsu A, Greish K, Maeda H. Elevating blood pressure as a strategy to increase tumor-targeted delivery of macromolecular drug SMANCS: cases of advanced solid tumors. Japanese Journal of Clinical Oncology. 2009; 39(11):756–66.

8 Arepally A, Chomas J, Kraitchman D, Hong K.  Quantification and Reduction of Reflux during Embolotherapy Using an Antireflux Catheter and Tantalum Microspheres: Ex Vivo Analysis. JVIR, 2013 24(4): 575–80.

Aravind Arepally is with the Division of Interventional Radiology at Piedmont Radiology,  Atlanta, USA. He receives a consulting fee from Surefire Medical and chairs the company’s Scientific Advisory Board