The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.tumor microenvironment | desmoplastic tumors | pancreatic ductal adenocarcinoma | mathematical modeling | sonic hedgehog pathway E levated interstitial fluid pressure (IFP) and solid stress are hallmarks of the mechanical microenvironment of solid tumors (1). IFP is the isotropic stress (i.e., applied equally in all directions) exerted by the fluid, whereas solid stress is exerted by the nonfluid components. In 1950, the work by Young et al. (2) provided the first measurements of IFP in tumors growing in rabbits and found it to be elevated compared with IFP in normal testicular tissue. However, the implications of this interstitial hypertension for tumor progression and treatment were not fully revealed for nearly four decades. In 1988, we developed a mathematical model that showed that IFP is uniformly elevated throughout the bulk of a tumor and precipitously drops to normal values in the tumor margin, causing a steep pressure gradient (3,4). Based on the model's results, we predicted that diffusion rather than convection would be the dominant mode of transport within tumors because of nearly uniform pressure within the tumor. Furthermore, we predicted that the steep pressure gradients in the periphery would cause fluid leaking from the blood vessels located in the tumor margin-but not from the vessels in the tumor interiorto ooze into the surrounding normal tissue. This oozing fluid would facilitate transport of growth factors and cancer cells into the surrounding tissue-fueling tumor growth, progression, and lymphatic metastasis. In subsequent years, we confirmed th...
The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan-a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity-can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors. drug delivery | matrix modifier | thrombospondin-1 | transforming growth factor β | transport A lthough nanotherapeutics have offered new hope for cancer treatment, their clinical efficacy is modest (1-4). This is partly because their penetration is hindered, especially in fibrotic tumors, where the small interfibrillar spacing in the interstitium retards the movement of particles larger than 10 nm (5-8). Pegylated liposomal doxorubicin (Doxil), approved by the Food and Drug Administration, and oncolytic viruses, currently in multiple clinical trials, represent two nanotherapeutics whose size (∼100 nm) hinders their intratumoral distribution and therapeutic effectiveness (9). Matrix modifiers such as bacterial collagenase, relaxin, and matrix metalloproteinase-1 and -8 have been used to modify the collagen or proteoglycan network in tumors and have improved the efficacy of intratumorally (i.t.) injected oncolytic viruses (8,(10)(11)(12)(13). However, these agents may produce normal tissue toxicity (e.g., bacterial collagenase) or increase the risk of tumor progression (e.g., relaxin, matrix metalloproteinases).Losartan (14)-approved to control hypertension in patients -does not have many of these safety risks. Furthermore, in addition to its antihypertensive properties, losartan is also an antifibrotic agent that has been shown to reduce the incidence of cardiac and renal fibrosis (15, 16). The antifibrotic effects of losartan are caused, in part, by the suppression of active transforming growth factor-β1 (TGF-β1) levels via an angiotensin II type I receptor (AGTR1)-mediated down-regulation of TGF-β1 activators such as thrombospondin-1 (TSP-1) (15-19). Using a dose that has minimal effects on mean arterial blood pressure (MABP), we show that losartan reduces collagen I levels in four tumor models-a spontaneous mouse mammary carcinoma (FVB MMTV PyVT), an orthotopic pancreatic adenocarcinoma (L3.6pl), and s.c. implanted fibrosarcoma (HSTS26T) and melanoma (Mu89). Losartan also improves the intratumoral penetration of nanoparticles injected i.t. or i.v.Based on these results, we tested how losartan would affect the distributi...
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