Review: Inhibitory potential of low molecular weight Heparin in cell adhesion; emphasis on tumor metastasis

Ejaz, Umer; Akhtar, Fahad; Xue, Jinbing; Wan, Xinyu; Zhang, Tong; He, Shuang-Hui

doi:10.1016/j.ejphar.2020.173778

Cited by 13 publications

(6 citation statements)

References 83 publications

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“…Similarly, factors of the coagulation cascade, as factor V, have demonstrated a role in the interaction of the CTC with the vascular endothelium and the efficiency of metastasis 29 . From a therapeutic perspective, anticoagulant drugs as low molecular weight heparin and warfarin, contributing to reduce blood viscosity, have shown antitumor and antimetastatic activity 30,31 . In addition to viscosity, the potential anti-metastatic effects include the modulation of growth factors and anticoagulant activity, and the inhibition of selectin-mediated interactions of tumour cells with leukocytes, platelets and endothelial cells mediating the hematogenous metastasis 32 .…”

Section: Resultsmentioning

confidence: 99%

Haemodynamic-dependent arrest of circulating tumour cells at large blood vessel bifurcations as new model for metastasis

Casas-Arozamena

Otero-Cacho

Carnero

et al. 2021

Sci Rep

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Homing of circulating tumour cells (CTC) at distant sites represents a critical event in metastasis dissemination. In addition to physical entrapment, probably responsible of the majority of the homing events, the vascular system provides with geometrical factors that govern the flow biomechanics and impact on the fate of the CTC. Here we mathematically explored the distribution of velocities and the corresponding streamlines at the bifurcations of large blood vessel and characterized an area of low-velocity at the carina of bifurcation that favours the residence of CTC. In addition to this fluid physics effect, the adhesive capabilities of the CTC provide with a biological competitive advantage resulting in a marginal but systematic arrest as evidenced by dynamic in vitro recirculation in Y-microchannels and by perfusion in in vivo mice models. Our results also demonstrate that viscosity, as a main determinant of the Reynolds number that define flow biomechanics, may be modulated to limit or impair CTC accumulation at the bifurcation of blood vessels, in agreement with the apparent positive effect observed in the clinical setting by anticoagulants in advanced oncology disease.

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Section: Resultsmentioning

confidence: 99%

Haemodynamic-dependent arrest of circulating tumour cells at large blood vessel bifurcations as new model for metastasis

Casas-Arozamena

Otero-Cacho

Carnero

et al. 2021

Sci Rep

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“…57 This is analogous to the function of heparin and other GAGs in tissues, 58 where growth factors signals and gradients are regulated by their participation in the bulk COL matrix. 59 However, heparin, as a single component, is unsupportive of robust cell adhesion, 60,61 limiting its applications in cell culture. Different studies employing HEP/COL for MSCs manufacturing have shown better outcomes for adhesion, growth, secretome, and senescence, among others, 21,22,62 but no specific mechanisms have been explored.…”

Section: Discussionmentioning

confidence: 99%

Heparin–collagen I bilayers stimulate FAK/ERK½ signaling via α2β1 integrin to support the growth and anti‐inflammatory potency of mesenchymal stromal cells

Cifuentes,

Domenech

2023

J Biomedical Materials Res

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Understanding mesenchymal stromal cells (MSCs) growth mechanisms in response to surface chemistries is essential to optimize culture methods for high‐quality and robust cell yields in cell manufacturing applications. Heparin (HEP) and collagen 1 (COL) substrates have been reported to enhance cell adhesion, growth, viability, and secretory potential in MSCs. However, the biomolecular mechanisms underlying the benefits of combined HEP/COL substrates are unknown. This work used HEP/COL bilayered surfaces to investigate the role of integrin‐HEP interactions in the advantages of MSC culture. The layer‐by‐layer approach (LbL) was used to create HEP/COL bilayers, which were made up of stacks of 8 and 9 layers that combined HEP and COL in an alternate arrangement. Surface spectroscopic investigations and laser scanning microscopy evaluations verified the biochemical fingerprint of each component and a total stacked bilayer thickness of roughly 150 nm. Cell growth and apoptosis in response to IC50 and IC75 levels of BTT‐3033 and Cilengitide, α2β1 and αvβ3 integrin inhibitors respectively, were evaluated on HEP/COL coated surfaces using two bone marrow‐derived MSC donors. While integrin activity did not affect cell growth rates, it significantly affected cell adhesion and apoptosis on HEP/COL surfaces. HEP‐ending HEP/COL surfaces significantly increased FAK‐ERK½ phosphorylation and endogenous cell COL deposition compared to COL, COL‐ending HEP/COL and uncoated surfaces. BTT‐3033 but not Cilengitide treatment markedly affected FAK‐ERK½ activity levels on HEP‐ending HEP/COL surfaces supporting a major role for α2β1 activity. BTT‐3033 treatment on HEP‐ending bilayers reduced MSC‐mediated macrophage inhibitory activity and altered the cytokine profile of co‐cultures. Overall, this study supports a novel role for HEP in regulating the survival and potency of MSCs via enhancing the α2β1‐FAK‐ERK½ signaling mechanism.

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“…Due to their hypercoagulable state, many cancer patients are given antithrombotic drugs [ 328 ]. A common anticoagulant given to cancer patients is low molecular weight heparin (LMWH), which has been reported to inhibit tumor metastasis [ 366 ]. Preclinical and clinical studies support that LMWHs can also significantly inhibit inflammation and fibrosis [ 367 , 368 , 369 ].…”

Section: Role Of Tgf-βs In the Pathophysiology Of Fibrosismentioning

confidence: 99%

Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective

Danielpour

2024

Pharmaceuticals

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The TGF-β family is a group of 25 kDa secretory cytokines, in mammals consisting of three dimeric isoforms (TGF-βs 1, 2, and 3), each encoded on a separate gene with unique regulatory elements. Each isoform plays unique, diverse, and pivotal roles in cell growth, survival, immune response, and differentiation. However, many researchers in the TGF-β field often mistakenly assume a uniform functionality among all three isoforms. Although TGF-βs are essential for normal development and many cellular and physiological processes, their dysregulated expression contributes significantly to various diseases. Notably, they drive conditions like fibrosis and tumor metastasis/progression. To counter these pathologies, extensive efforts have been directed towards targeting TGF-βs, resulting in the development of a range of TGF-β inhibitors. Despite some clinical success, these agents have yet to reach their full potential in the treatment of cancers. A significant challenge rests in effectively targeting TGF-βs’ pathological functions while preserving their physiological roles. Many existing approaches collectively target all three isoforms, failing to target just the specific deregulated ones. Additionally, most strategies tackle the entire TGF-β signaling pathway instead of focusing on disease-specific components or preferentially targeting tumors. This review gives a unique historical overview of the TGF-β field often missed in other reviews and provides a current landscape of TGF-β research, emphasizing isoform-specific functions and disease implications. The review then delves into ongoing therapeutic strategies in cancer, stressing the need for more tools that target specific isoforms and disease-related pathway components, advocating mechanism-based and refined approaches to enhance the effectiveness of TGF-β-targeted cancer therapies.

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Review: Inhibitory potential of low molecular weight Heparin in cell adhesion; emphasis on tumor metastasis

Cited by 13 publications

References 83 publications

Haemodynamic-dependent arrest of circulating tumour cells at large blood vessel bifurcations as new model for metastasis

Haemodynamic-dependent arrest of circulating tumour cells at large blood vessel bifurcations as new model for metastasis

Heparin–collagen I bilayers stimulate FAK/ERK½ signaling via α2β1 integrin to support the growth and anti‐inflammatory potency of mesenchymal stromal cells

Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective

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