The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou, Christiana M.; Panagi, Myrofora; Stylianopoulos, Triantafyllos; Papageorgis, Panagiotis

doi:10.3390/cancers13092053

Cited by 201 publications

(141 citation statements)

References 207 publications

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“…Malignancy of cancer cells and its ability to metastasize strongly depend on the tumor microenvironment [ 55 ]. PARP-1 plays an important role in the functioning of the tumor microenvironment, participating in angiogenesis as well as in the formation of a tumor-associated stroma [ 56 ].…”

Section: Parp-1 and Oncological Diseasesmentioning

confidence: 99%

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Feofanov

Studitsky

2021

IJMS

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Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in processes of cell cycle regulation, DNA repair, transcription, and replication. Hyperactivity of PARP-1 induced by changes in cell homeostasis promotes development of chronic pathological processes leading to cell death during various metabolic disorders, cardiovascular and neurodegenerative diseases. In contrast, tumor growth is accompanied by a moderate activation of PARP-1 that supports survival of tumor cells due to enhancement of DNA lesion repair and resistance to therapy by DNA damaging agents. That is why PARP inhibitors (PARPi) are promising agents for the therapy of tumor and metabolic diseases. A PARPi family is rapidly growing partly due to natural polyphenols discovered among plant secondary metabolites. This review describes mechanisms of PARP-1 participation in the development of various pathologies, analyzes multiple PARP-dependent pathways of cell degeneration and death, and discusses representative plant polyphenols, which can inhibit PARP-1 directly or suppress unwanted PARP-dependent cellular processes.

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Section: Parp-1 and Oncological Diseasesmentioning

confidence: 99%

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Feofanov

Studitsky

2021

IJMS

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“…Cell invasion and migration are finely regulated processes that are critical in cancer progression and metastasis ( Entschladen et al, 2004 ). Not only the driving signaling in tumor cells, the crosstalk between tumor cells and TME is also responsible for tumor cell invasion and migration ( Neophytou et al, 2021 ). Tumor cells, TAMs, and other stromal cells within TME communicate with each other through the secretion of exosomes, carrying various molecules.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived Exosomal Protein Tyrosine Phosphatase Receptor Type O Polarizes Macrophage to Suppress Breast Tumor Cell Invasion and Migration

Dong

Xie

Jiang

et al. 2021

Front. Cell Dev. Biol.

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Tumor-derived exosomes, containing multiple nucleic acids and proteins, have been implicated to participate in the interaction between tumor cells and microenvironment. However, the functional involvement of phosphatases in tumor-derived exosomes is not fully understood. We and others previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) acts as a tumor suppressor in multiple cancer types. In addition, its role in tumor immune microenvironment remains elusive. Bioinformatical analyses revealed that PTPRO was closely associated with immune infiltration, and positively correlated to M1-like macrophages, but negatively correlated to M2-like macrophages in breast cancer tissues. Co-cultured with PTPRO-overexpressing breast cancer cells increased the proportion of M1-like tumor-associated macrophages (TAMs) while decreased that of M2-like TAMs. Further, we observed that tumor-derived exosomal PTPRO induced M1-like macrophage polarization, and regulated the corresponding functional phenotypes. Moreover, tumor cell-derived exosomal PTPRO inhibited breast cancer cell invasion and migration, and inactivated STAT signaling in macrophages. Our data suggested that exosomal PTPRO inhibited breast cancer invasion and migration by modulating macrophage polarization. Anti-tumoral effect of exosomal PTPRO was mediated by inactivating STAT family in macrophages. These findings highlight a novel mechanism of tumor invasion regulated by tumor-derived exosomal tyrosine phosphatase, which is of translational potential for the therapeutic strategy against breast cancer.

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“…The TME plays a crucial role in tumor growth, metastasis and development of MDR. The TME consists of immune cells, fibroblasts and endothelial cells that communicate with cancer cells through paracrine signaling [127]. Immune cells present in the TME can activate or inhibit apoptotic pathways and affect response to therapy [128].…”

Section: Implications Of the Tme In Apoptosis And Mdrmentioning

confidence: 99%

Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance

Neophytou

Trougakos

Erin

et al. 2021

Cancers

Self Cite

165

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The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward agents with different function and/or structure. Proteins implicated in the intrinsic pathway of apoptosis, including the Bcl-2 superfamily and Inhibitors of Apoptosis (IAP) family members, as well as their regulator, tumor suppressor p53, have been implicated in the development of MDR in many cancer types. The PI3K/AKT pathway is pivotal in promoting survival and proliferation and is often overactive in MDR tumors. In addition, the tumor microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit apoptosis in cancer cells and reduce the effectiveness of different anti-cancer drugs. In this review, we describe the main alterations that occur in apoptosis-and related pathways to promote MDR. We also summarize the main therapeutic approaches against resistant tumors, including agents targeting Bcl-2 family members, small molecule inhibitors against IAPs or AKT and agents of natural origin that may be used as monotherapy or in combination with conventional therapeutics. Finally, we highlight the potential of therapeutic exploitation of epigenetic modifications to reverse the MDR phenotype.

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The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Cited by 201 publications

References 207 publications

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Tumor-Derived Exosomal Protein Tyrosine Phosphatase Receptor Type O Polarizes Macrophage to Suppress Breast Tumor Cell Invasion and Migration

Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance

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