Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.

/pdf/extracellular-matrix-and-its-therapeutic-potential-for-4mannczf4y.pdf

Extracellular matrix and its therapeutic potential for cancer treatment

Doxorubicin (DOX) as a traditional chemotherapy drug is restricted in clinical applications due to its poor therapeutic activity and severe side effects. Herein, we prepared a metal–organic framework (MOF) MIL-100 by a microwave-assisted synthesis and DOX was loaded in MIL-100 and then, hyaluronic acid (HA) was modified on the surface of MIL-100 to give DMH NPs. The DMH NPs possessed the following advantages: (1) MIL-100 could serve as a drug carrier with a high DOX loading efficiency; MIL-100 could also generate a hydroxyl radical (˙OH) in the presence of H2O2 for chemodynamic therapy (CDT) via a Fenton-like reaction. (2) To improve the dispersibility of MIL-100, HA was modified on the surface of MIL-100, which could endow MIL-100 with a targeting ability towards tumor tissues. (3) DMH NPs could enhance antitumor efficacy and reduce drug-related toxicity though the combination of chemotherapy and chemodynamic therapy. DMH NPs have enormous potential as a candidate for reducing the systemic toxicity and improving the treatment effect for breast cancer.

Doxorubicin-loaded nanoscale metal-organic framework for tumor-targeting combined chemotherapy and chemodynamic therapy.

Folic acid-modified Exosome-PH20 enhances the efficiency of therapy via modulation of the tumor microenvironment and directly inhibits tumor cell metastasis.

The extracellular matrix (ECM) plays an increasingly recognised role in the development and progression of cancer. Whilst significant progress has been made in targeting aspects of the tumour microenvironment such as tumour immunity and angiogenesis, there are no therapies that address the cancer ECM. Importantly, immune function relies heavily on the structure, physics and composition of the ECM, indicating that cancer ECM and immunity are mechanistically inseparable. In this review we highlight mechanisms by which the ECM shapes tumour immunity, identifying potential therapeutic targets within the ECM. These data indicate that to fully realise the potential of cancer immunotherapy, the cancer ECM requires simultaneous consideration.

https://www.mdpi.com/2072-6694/12/11/3331/pdf

Cancer Extracellular Matrix Proteins Regulate Tumour Immunity.

Hyaluronic acid (HA) is found in various tumor tissues, and is considered tumor-associated extracellular matrix (ECM). Within this tumor-associated ECM, stromal cells, especially immune cells, are involved in tumor progression. However, the effects of tumor-associated ECM on the characteristics of immune cells remain unexplored. Therefore, we studied the triggering effect of HA on spontaneous M2-like polarity of monocytes/macrophages using HA-mixed collagen (HA-COL) matrix. In the presence of HA, expression of the HA receptor (CD44) and M2 polarity-related genes was upregulated in human monocytes (THP-1 cells). We confirmed the CD44-mediated activation of STAT3 in THP-1 cells cultured in an HA-rich environment. Furthermore, when we induced the THP-1 cells to differentiate into cells with M1 or M2 polarity within an HA-rich environment, the HA-rich environment influenced the direction of induction. Our findings might improve understanding of the crosstalk between immune cells and tumor-associated ECM, and facilitate development of tumor immunotherapy strategies.

Hyaluronic acid-based extracellular matrix triggers spontaneous M2-like polarity of monocyte/macrophage.

Feature-based translation of CAD models with macro-parametric approach: issues of feature mapping, persistent naming, and constraint translation

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Hyaluronic acid-based extracellular matrix triggers spontaneous M2-like polarity of monocyte/macrophage.

Feature-based translation of CAD models with macro-parametric approach: issues of feature mapping, persistent naming, and constraint translation