Tumor cells reside in a highly complex and heterogeneous tumor microenvironment (TME), which is composed of a myriad of genetically stable non-cancer cells, including fibroblasts, immune cells, endothelial cells, and epithelial cells, and a tumor-specific extracellular matrix (ECM). Cancer-associated fibroblasts (CAFs), as an abundant and active stromal cell population in the TME, function as the signaling center and remodeling machine to aid the creation of a desmoplastic tumor niche. Although there is no denial that the TME and CAFs may have anti-tumor effects as well, a great deal of findings reported in recent years have convincingly revealed the tumor-promoting effects of CAFs and CAF-derived ECM proteins, enzymes, chemical factors and other downstream effectors. While there is growing enthusiasm for the development of CAF-targeting therapies, a better understanding of the complexities of CAF-ECM and CAF-cancer cell interactions is necessary before novel therapeutic strategies targeting the malignant tumor “soil” can be successfully implemented in the clinic.

/pdf/cancer-associated-fibroblasts-build-and-secure-the-tumor-4m7695bena.pdf

Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment.

Cancer microenvironment is critical for tumorigenesis and cancer progression. The extracellular matrix (ECM) interacts with tumor and stromal cells to promote cancer cells proliferation, migration, invasion, angiogenesis and immune evasion. Both ECM itself and ECM stiffening-induced mechanical stimuli may activate cell membrane receptors and mechanosensors such as integrin, Piezo1 and TRPV4, thereby modulating the malignant phenotype of tumor and stromal cells. A better understanding of how ECM stiffness regulates tumor progression will contribute to the development of new therapeutics. The rapidly expanding evidence in this research area suggests that the regulators and effectors of ECM stiffness represent potential therapeutic targets for cancer. This review summarizes recent work on the regulation of ECM stiffness in cancer, the effects of ECM stiffness on tumor progression, cancer immunity and drug resistance. We also discuss the potential targets that may be druggable to intervene ECM stiffness and tumor progression. Based on these advances, future efforts can be made to develop more effective and safe drugs to interrupt ECM stiffness-induced oncogenic signaling, cancer progression and drug resistance. 

https://jhoonline.biomedcentral.com/track/pdf/10.1186/s13045-022-01252-0

Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy

Several biomedical analyses are performed on particular types of cells present in body samples or using functionalized microparticles. Success in such analyses depends on the ability to separate or isolate the target cells or microparticles from the rest of the sample. In conventional procedures, multiple pieces of equipment, such as centrifuges, magnets, and macroscale filters, are used for such purposes, which are time-consuming, associated with human error, and require several operational steps. In the past two decades, there has been a tendency to develop microfluidic techniques, so-called lab-on-a-chip, to miniaturize and automate these procedures. The processes used for the separation and isolation of the cells and microparticles are scaled down into a small microfluidic chip, requiring very small amounts of sample. Differences in the physical and biological properties of the target cells from the other components present in the sample are the key to the development of such microfluidic techniques. These techniques are categorized as filtration-, hydrodynamic-, dielectrophoretic-, acoustic- and magnetic-based methods. Here we review the microfluidic techniques developed for sorting, separation, and isolation of cells and microparticles for biomedical applications. The mechanisms behind such techniques are thoroughly explained and the applications in which these techniques have been adopted are reviewed.

A review of sorting, separation and isolation of cells and microbeads for biomedical applications: microfluidic approaches.

The recent demonstration that primary cells from the liver can be expanded in vitro as organoids holds enormous promise for regenerative medicine and disease modelling. The use of three-dimensional (3D) cultures based on ill-defined and potentially immunogenic matrices, however, hampers the translation of liver organoid technology into real-life applications. We here use chemically defined hydrogels for the efficient derivation of both mouse and human hepatic organoids. Organoid growth is found to be highly stiffness-sensitive, a mechanism independent of acto-myosin contractility and requiring instead activation of the Src family of kinases (SFKs) and yes-associated protein 1 (YAP). Aberrant matrix stiffness, on the other hand, results in compromised proliferative capacity. Finally, we demonstrate the establishment of biopsy-derived human liver organoids without the use of animal components at any step of the process. Our approach thus opens up exciting perspectives for the establishment of protocols for liver organoid-based regenerative medicine.

Mechano-modulatory synthetic niches for liver organoid derivation

Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.

/pdf/pulmonary-fibrosis-as-a-result-of-acute-lung-inflammation-2qxipp1q.pdf

Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches

Periostin promotes liver fibrogenesis by activating lysyl oxidase in hepatic stellate cells

The enrichment of viable cells is an essential step to obtain effective products for cell therapy. While procedures exist to characterize the viability of cells, most methods to exclude nonviable cells require the use of density gradient centrifugation or antibody-based cell sorting with molecular labels of cell viability. We report a label-free microfluidic technique to separate live and dead cells that exploits differences in cellular stiffness. The device uses a channel with repeated ridges that are diagonal with respect to the direction of cell flow. Stiff nonviable cells directed through the channel are compressed and translated orthogonally to the channel length, while soft live cells follow hydrodynamic flow. As a proof of concept, Jurkat cells are enriched to high purity of viable cells by a factor of 185-fold. Cell stiffness was validated as a sorting parameter as nonviable cells were substantially stiffer than live cells. To highlight the utility for hematopoietic stem cell transplantation, frozen samples of cord blood were thawed and the purity of viable nucleated cells was increased from 65% to over 94% with a recovery of 73% of the viable cells. Thus, the microfluidic stiffness sorting can simply and efficiently obtain highly pure populations of viable cells.

Microfluidic Sorting of Cells by Viability Based on Differences in Cell Stiffness

Cancers consist of a heterogeneous populations of cells that may respond differently to treatment through drug-resistant sub-populations. The scarcity of these resistant sub-populations makes it challenging to understand how to counter their resistance. We report a label-free microfluidic approach to separate cancer cells treated with chemotherapy into sub-populations enriched in chemoresistant and chemosensitive cells based on the differences in cellular stiffness. The sorting approach enabled analysis of the molecular distinctions between resistant and sensitive cells. Consequently, the role of multiple mechanisms of drug resistance was identified, including decreased sensitivity to apoptosis, enhanced metabolism, and extrusion of drugs, and, for the first time, the role of estrogen receptor in drug resistance of leukemia cells. To validate these findings, several inhibitors for the identified resistance pathways were tested with chemotherapy to increase cytotoxicity sevenfold. Thus, microfluidic sorting can identify molecular mechanisms of drug resistance to examine heterogeneous responses of cancers to therapies.

/pdf/microfluidic-cell-sorting-by-stiffness-to-examine-35itg8mseh.pdf

Microfluidic cell sorting by stiffness to examine heterogenic responses of cancer cells to chemotherapy

To improve the survival rate of cancer patients, new diagnosis strategies are necessary to detect lower levels of cancer cells before and after treatment regimens The scarcity of diseased cells, particularly in residual disease after treatment, demands highly sensitive detection approaches or the ability to enrich the diseased cells in relation to normal cells We report a label-free microfluidic approach to enrich leukemia cells from healthy cells using inherent differences in cell biophysical properties The microfluidic device consists of a channel with an array of diagonal ridges that recurrently compress and translate flowing cells in proportion to cell stiffness Using devices optimized for acute T cell leukemia model Jurkat, the stiffer white blood cells were translated orthogonally to the channel length, while softer leukemia cells followed hydrodynamic flow The device enriched Jurkat leukemia cells from white blood cells with an enrichment factor of over 760 The sensitivity, specificity, and accuracy of the device were found to be > 08 The values of sensitivity and specificity could be adjusted by selecting one or multiple outlets for analysis We demonstrate that low levels of Jurkat leukemia cells (1 in 10 4 white blood cells) could be more quickly detected using flow cytometry by using the stiffness sorting pre-enrichment In a second mode of operation, the device was implemented to sort resistive leukemia cells from both drug-sensitive leukemia cells and normal white blood cells Therefore, microfluidic biomechanical sorting can be a useful tool to enrich leukemia cells that may improve downstream analyses

/pdf/stiffness-based-enrichment-of-leukemia-cells-using-29l5zl5z8x.pdf

Stiffness based enrichment of leukemia cells using microfluidics.

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Papers

Periostin promotes liver fibrogenesis by activating lysyl oxidase in hepatic stellate cells

Microfluidic Sorting of Cells by Viability Based on Differences in Cell Stiffness

Microfluidic cell sorting by stiffness to examine heterogenic responses of cancer cells to chemotherapy

Stiffness based enrichment of leukemia cells using microfluidics.