Extracellular matrix and its therapeutic potential for cancer treatment

Huang, Jiacheng; Zhang, Lele; Wan, Dalong; Zhou, Lin; Zheng, Shusen; Lin, Shigang; Qiao, Yiting

doi:10.1038/s41392-021-00544-0

Cited by 429 publications

(303 citation statements)

References 555 publications

(226 reference statements)

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“…Emerging evidence suggests that the ECM and its remodeling products exert a crucial role in the regulation of the cancer-immunity cycle, and impact the mechanisms of resistance to immunotherapy [ 29 ]. In this view, the ECM proteins represent a promising therapeutic target and a route to discover new biomarkers that may be of value for the management of cancer patients [ 30 ]. In the present work, we showed that the expression of EMILIN2, which in melanoma is regulated by methylation, is variable among the patients and associated with the efficacy of anti-PD-L1 therapy.…”

Section: Discussionmentioning

confidence: 99%

The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

Fejza

Polano

Camicia

et al. 2021

IJMS

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The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

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Section: Discussionmentioning

confidence: 99%

The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

Fejza

Polano

Camicia

et al. 2021

IJMS

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“…Lately, there have been several reports regarding the importance of the tumor microenvironment, including that of the ECM, for therapeutic and diagnostic biomarkers [12,21]; however, the use of ECM biomarkers in CRCs has yet to be reviewed. Herein, we summarized several vital ECM proteins and representative enzymes responsible for development, remodeling, rearrangement, and manipulation of cellular functions such as MMPs, ADAMs, and LOXs, and their roles in both CRC development and progression.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Matrix Biomarkers in Colorectal Cancer

Kim

et al. 2021

IJMS

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The cellular microenvironment composition and changes therein play an extremely important role in cancer development. Changes in the extracellular matrix (ECM), which constitutes a majority of the tumor stroma, significantly contribute to the development of the tumor microenvironment. These alterations within the ECM and formation of the tumor microenvironment ultimately lead to tumor development, invasion, and metastasis. The ECM is composed of various molecules such as collagen, elastin, laminin, fibronectin, and the MMPs that cleave these protein fibers and play a central role in tissue remodeling. When healthy cells undergo an insult like DNA damage and become cancerous, if the ECM does not support these neoplastic cells, further development, invasion, and metastasis fail to occur. Therefore, ECM-related cancer research is indispensable, and ECM components can be useful biomarkers as well as therapeutic targets. Colorectal cancer specifically, is also affected by the ECM and many studies have been conducted to unravel the complex association between the two. Here we summarize the importance of several ECM components in colorectal cancer as well as their potential roles as biomarkers.

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“…Numerous drugs targeting the ECM have been described in the context of cancer (Huang et al [ 88 ] is an extensive review on the topic of therapeutic approaches to target ECM in cancer). One could envision that agents targeting the ECM of dormant cells could prevent their awakening or eliminate them, however a detailed description of the ECM matrisome of these dormant cells is needed to identify potential candidates that could be used to eliminate dormant cells.…”

Section: Outstanding Questions and Discussionmentioning

confidence: 99%

Remodeling the ECM: Implications for Metastasis and Tumor Dormancy

Martino

Akhter

Bravo-Cordero

2021

Cancers

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While most primary tumors can be effectively treated, therapeutics fail to efficiently eliminate metastases. Metastases arise from cancer cells that leave the primary tumor and seed distant sites. Recent studies have shown that cancer cells disseminate early during tumor progression and can remain dormant for years before they resume growth. In these metastatic organs, cancer cells reside in microenvironments where they interact with other cells, but also with the extracellular matrix (ECM). The ECM was long considered to be an inert, non-cellular component of tissues, providing their architecture. However, in recent years, a growing body of evidence has shown that the ECM is a key driver of cancer progression, and it can exert effects on tumor cells, regulating their metastatic fate. ECM remodeling and degradation is required for the early steps of the metastatic cascade: invasion, tumor intravasation, and extravasation. Similarly, ECM molecules have been shown to be important for metastatic outgrowth. However, the role of ECM molecules on tumor dormancy and their contribution to the dormancy-supportive niches is not well understood. In this perspective article, we will summarize the current knowledge of ECM and its role in tumor metastasis and dormancy. We will discuss how a better understanding of the individual components of the ECM niche and their roles mediating the dormant state of disseminated tumor cells (DTCs) will advance the development of new therapies to target dormant cells and prevent metastasis outgrowth.

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Extracellular matrix and its therapeutic potential for cancer treatment

Cited by 429 publications

References 555 publications

The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

Extracellular Matrix Biomarkers in Colorectal Cancer

Remodeling the ECM: Implications for Metastasis and Tumor Dormancy

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