Interstitial Fluid Pressure Correlates Clinicopathological Factors of Lung Cancer

Mori, Takeshi; Kinoshita, Toshihiko; Shibata, Hidekatsu; Ikeda, Koei; Shiraishi, Kenji; Suzuki, Makoto; Iyama, Ken Ichi

doi:10.5761/atcs.oa.14-00208

Cited by 16 publications

(8 citation statements)

References 17 publications

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“… 6 , 7 It is interesting that recent studies have emphasized the role of increasing interstitial fluid pressure (IFP) in metastasis. 8 , 9 , 10 Given that the high degree of mechanical stress caused by obstruction continuously stimulates CCA cells in tumor tissue formation, whether the stress is related to the CCA metastasis needs to be studied.…”

Section: Introductionmentioning

confidence: 99%

Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis

Zhu

Qian

Han

et al. 2021

Molecular Therapy - Nucleic Acids

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Tumor metastasis is one of the major factors for the high mortality in cholangiocarcinoma (CCA), but its underlying mechanisms are not fully understood. Here, we report that Piezo-type mechanosensitive ion channel component 1 (Piezo 1) is detected to be significantly upregulated in CCA tissues, which is linked to a poor prognosis in patients, suggesting that Piezo 1 may act in a pro-metastatic role in CCA development. Piezo 1 is activated through 20% simulated physiological stretch, and deleting Piezo 1 impedes epithelial-to-mesenchymal transition (EMT) of CCA cells, as well as impairing their metastatic capacity in vitro and in vivo . Mechanistically, the activation of Piezo 1 results in large amounts of Yes-associated protein 1 (YAP) translocated into the nucleus from the cytoplasm, and thus the motility of CCA cells is significantly increased. These findings indicate that mechanical stimulation induces Piezo 1 activation, which might be involved in CCA metastasis via the Hippo/YAP signaling axis. Therefore, Piezo 1 and its downstream effectors may be a novel therapeutic target for CCA treatment.

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Section: Introductionmentioning

confidence: 99%

Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis

Zhu

Qian

Han

et al. 2021

Molecular Therapy - Nucleic Acids

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“…It has been well recognized that the microenvironment of solid tumors commonly harbors elevated IFP, which is thought to be based on high cell density, abnormal extracellular matrix, vascular abnormalities, and poor venous and lymphatic drainage [ 59 , 60 ]. High IFP may impede therapeutic drug delivery to the tumor tissue, and it has been associated with lower treatment response and poor prognosis in several solid cancer types [ 59 , 60 , 61 ]. In comparison, liquid tumors such as AML—where tumor cells are distributed in the systemic circulation and where the vasculature of their bone marrow niche is different from the vasculature in other organs [ 62 ]—are more readily and more homogeneously accessible to drugs present in the blood stream.…”

Section: Discussionmentioning

confidence: 99%

NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity

Chen

Minea

Swenson

et al. 2022

Cancers

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Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair enzyme) in tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called NEO212, where TMZ was covalently conjugated to perillyl alcohol (a naturally occurring monoterpene). NEO212 has revealed robust therapeutic activity in a variety of preclinical cancer models, including AML. In the current study, we investigated its impact on a panel of human AML cell lines and found that it exerted cytotoxic potency even against MGMT-positive cells that were highly resistant to TMZ. Furthermore, NEO212 strongly stimulated the expression of a large number of macrophage-associated marker genes, including CD11b/ITGAM. This latter effect could not be mimicked when cells were treated with TMZ or an equimolar mix of individual agents, TMZ plus perillyl alcohol. The superior cytotoxic impact of NEO212 appeared to involve down-regulation of MGMT protein levels. In a mouse model implanted with TMZ-resistant, MGMT-positive AML cells, two 5-day cycles of 25 mg/kg NEO212 achieved an apparent cure, as mice survived >300 days without any signs of disease. In parallel toxicity studies with rats, a 5-day cycle of 200 mg/kg NEO212 was well tolerated by these animals, whereas animals that were given 200 mg/kg TMZ all died due to severe leukopenia. Together, our results show that NEO212 exerts pleiotropic effects on AML cells that include differentiation, proliferation arrest, and eventual cell death. In vivo, NEO212 was well tolerated even at dosages that far exceed the therapeutic need, indicating a large therapeutic window. These results present NEO212 as an agent that should be considered for development as a therapeutic agent for AML.

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“…In the present study, changes in pressure homeostasis and collagen organization could both influence tumor growth and invasion. Of interest, increased tumor PIF has been linked to tumor aggressiveness in some human cancers [ 9 , 49 ], and is an independent poor prognostic factor in cervical cancer [ 10 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Stromal integrin α11-deficiency reduces interstitial fluid pressure and perturbs collagen structure in triple-negative breast xenograft tumors

et al. 2019

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BackgroundCancer progression is influenced by a pro-tumorigenic microenvironment. The aberrant tumor stroma with increased collagen deposition, contractile fibroblasts and dysfunctional vessels has a major impact on the interstitial fluid pressure (PIF) in most solid tumors. An increased tumor PIF is a barrier to the transport of interstitial fluid into and within the tumor. Therefore, understanding the mechanisms that regulate pressure homeostasis can lead to new insight into breast tumor progression, invasion and response to therapy. The collagen binding integrin α11β1 is upregulated during myofibroblast differentiation and expressed on fibroblasts in the tumor stroma. As a collagen organizer and a probable link between contractile fibroblasts and the complex collagen network in tumors, integrin α11β1 could be a potential regulator of tumor PIF.MethodsWe investigated the effect of stromal integrin α11-deficiency on pressure homeostasis, collagen organization and tumor growth using orthotopic and ectopic triple-negative breast cancer xenografts (MDA-MB-231 and MDA-MB-468) in wild type and integrin α11-deficient mice. PIF was measured by the wick-in-needle technique, collagen by Picrosirius Red staining and electron microscopy, and uptake of radioactively labeled 5FU by microdialysis. Further, PIF in heterospheroids composed of MDA-MB-231 cells and wild type or integrin α11-deficient fibroblasts was measured by micropuncture.ResultsStromal integrin α11-deficiency decreased PIF in both the orthotopic breast cancer models. A concomitant perturbed collagen structure was seen, with fewer aligned and thinner fibrils. Integrin α11-deficiency also impeded MDA-MB-231 breast tumor growth, but no effect was observed on drug uptake. No effects were seen in the ectopic model. By investigating the isolated effect of integrin α11-positive fibroblasts on MDA-MB-231 cells in vitro, we provide evidence that PIF regulation was mediated by integrin α11-positive fibroblasts.ConclusionWe hereby show the importance of integrin α11β1 in pressure homeostasis in triple-negative breast tumors, indicating a new role for integrin α11β1 in the tumor microenvironment. Our data suggest that integrin α11β1 has a pro-tumorigenic effect on triple-negative breast cancer growth in vivo. The significance of the local microenvironment is shown by the different effects of integrin α11β1 in the orthotopic and ectopic models, underlining the importance of choosing an appropriate preclinical model.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5449-z) contains supplementary material, which is available to authorized users.

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Interstitial Fluid Pressure Correlates Clinicopathological Factors of Lung Cancer

Cited by 16 publications

References 17 publications

Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis

Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis

NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity

Stromal integrin α11-deficiency reduces interstitial fluid pressure and perturbs collagen structure in triple-negative breast xenograft tumors

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