Response to Chauhan et al.: Interstitial Pressure and Vascular Collapse in Pancreas Cancer—Fluids and Solids, Measurement and Meaning

DelGiorno, Kathleen E.; Carlson, Markus A.; Osgood, Ryan J.; Provenzano, Paolo P.; Brockenbough, J. Scott; Thompson, Curtis B.; Shepard, H. Michael; Frost, Gregory I.; Potter, John D.; Hingorani, Sunil R.

doi:10.1016/j.ccr.2014.06.004

Cited by 26 publications

(33 citation statements)

References 6 publications

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“…The free-fluid pressures measured by the WN in autochthonous PDA 11,41 are even lower than those measured in xenografts or allografts. Despite the exhaustive studies of free-fluid pressure in these systems, 42,43 findings from these studies have produced a conceptual framework with little ability to explain the biophysical challenges in PDA.…”

Section: Interstitial Free Fluidmentioning

confidence: 64%

“…Contrary to expectations based on clinical and pathological characteristics, this method indicated that human pancreatic neuroendocrine tumors and liposarcomas have the highest solid stress, whereas spheroids from human PDA cell lines had among the lowest (more precise estimates of solid stress could not be made because the bulk and shear moduli were unknown). 21 Taken at face value, neither the low estimated solid stress nor the low free IFP measured with the WN in pancreas cancer models 11,41 can explain the vascular collapse observed in autochthonous PDAs.…”

Section: Solids and Cellsmentioning

confidence: 94%

“…We have shown that a reconfigured PC-in-needle (ie, a PC sheathed inside a needle to shield it from solid tissue) gave the same readings as the PC itself, excluding the possibility of solid pressure artifacts in this context. 11 …”

Section: Interstitial Gel Fluidmentioning

confidence: 99%

“…Specifically, we describe mechanisms behind the substantial increases in interstitial pressures in PDA, which can greatly exceed mean vascular pressures and compromise the efficacy of traditional chemotherapeutics. 10,11 Targeted enzymatic degradation of hyaluronic acid (HA) reverses these increases in pressure, allowing collapsed vessels to reopen and improving perfusion. 10,12 Despite extensive studies of interstitial fluid pressure (IFP) that have spanned more than half a century, the sources of pressures most germane to impaired solute delivery in solid tumors are still debated, as are the most accurate ways to characterize and measure them.…”

mentioning

confidence: 99%

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Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma

2016

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The microenvironment influences the pathogenesis of solid tumors and plays an outsized role in some. Our understanding of the stromal response to cancers, particularly pancreatic ductal adenocarcinoma, has evolved from that of host defense to tumor offense. We know that most, although not all, of the factors and processes in the microenvironment support tumor epithelial cells. This reappraisal of the roles of stromal elements has also revealed potential vulnerabilities and therapeutic opportunities to exploit. The high concentration in the stroma of the glycosaminoglycan hyaluronan, together with the large gel-fluid phase and pressures it generates, were recently identified as primary sources of treatment resistance in pancreas cancer. Whereas the relatively minor role of free interstitial fluid in the fluid mechanics and perfusion of tumors has been long appreciated, the less mobile, gel-fluid phase has been largely ignored for historical and technical reasons. The inability of classic methods of fluid pressure measurement to capture the gel-fluid phase, together with a dependence on xenograft and allograft systems that inaccurately model tumor vascular biology, has led to an undue emphasis on the role of free fluid in impeding perfusion and drug delivery and an almost complete oversight of the predominant role of the gel-fluid phase. We propose that a hyaluronan-rich, relatively immobile gel-fluid phase induces vascular collapse and hypoperfusion as a primary mechanism of treatment resistance in pancreas cancers. Similar properties may be operant in other solid tumors as well, so revisiting and characterizing fluid mechanics with modern techniques in other autochthonous cancers may be warranted.

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Section: Interstitial Free Fluidmentioning

confidence: 64%

Section: Solids and Cellsmentioning

confidence: 94%

Section: Interstitial Gel Fluidmentioning

confidence: 99%

mentioning

confidence: 99%

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Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma

2016

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“…Cells meet this 1uM AZ2014 by upregulating de novo synthetic metabolic pathways (Elstrom et al, 2004;Engelman et al, 2006) or, alternatively, by scavenging and reusing macromolecules (White, 2013). The latter can be critical in a nutrient-restrictive tumor microenvironment, such as in PDAC, where nutrient delivery is poor due to the extensive fibrosis and deficient vasculature (Provenzano et al, 2012;Chauhan et al, 2014;DelGiorno et al, 2014). The decision to commit to de novo synthesis or scavenging appears to be, at least in part, governed by oncogenic signaling (Pavlova and Thompson, 2016).…”

Section: Discussionmentioning

confidence: 99%

Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition

et al. 2020

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The Biophysics of Cancer: Emerging Insights from Micro‐ and Nanoscale Tools

Beshay

Cortes-Medina

Menyhert

et al. 2021

Advanced NanoBiomed Research

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Cancer is a complex and dynamic disease that is aberrant both biologically and physically. There is growing appreciation that physical abnormalities with both cancer cells and their microenvironment that span multiple length scales are important drivers for cancer growth and metastasis. The scope of this review is to highlight the key advancements in micro‐ and nanoscale tools for delineating the cause and consequences of the aberrant physical properties of tumors. Herein, the following three important physical aspects of cancer are focused: 1) solid mechanical properties, 2) fluid mechanical properties, and 3) mechanical alterations to cancer cells. Beyond posing physical barriers to the delivery of cancer therapeutics, these properties are also known to influence numerous biological processes, including cancer cell invasion and migration leading to metastasis, and response and resistance to therapy. There is a comment on how micro‐ and nanoscale tools have transformed the fundamental understanding of the physical dynamics of cancer progression and their potential for bridging toward future applications at the interface of oncology and physical sciences.

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Response to Chauhan et al.: Interstitial Pressure and Vascular Collapse in Pancreas Cancer—Fluids and Solids, Measurement and Meaning

Cited by 26 publications

References 6 publications

Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma

Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma

Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition

The Biophysics of Cancer: Emerging Insights from Micro‐ and Nanoscale Tools

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