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Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting.

ABSTRACT: There are few tumor cell subpopulations with stem cell characteristics in tumor tissue, defined as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs), which can reconstruct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation. The microenvironment that CSCs depend on consists of various cellular components and corresponding medium components. Among these factors existing at a variety of levels and forms, cytokine networks and numerous signal pathways play an important role in signaling transduction. These factors promote or maintain cancer cell stemness, and participate in cancer recurrence, metastasis, and resistance. This review aims to summarize the recent molecular data concerning the multilayered relationship between CSCs and CSC-favorable microenvironments. We also discuss the therapeutic implications of targeting this synergistic interplay, hoping to give an insight into targeting cancer cell stemness for tumor therapy and prognosis.

SUBMITTER: Guo Q

PROVIDER: S-EPMC10825311 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting.

Guo Qianqian Q Zhou Yi Y Xie Tianyuan T Yuan Yin Y Li Huilong H Shi Wanjin W Zheng Lufeng L Li Xiaoman X Zhang Wenzhou W

Genes & diseases 20230719 3

There are few tumor cell subpopulations with stem cell characteristics in tumor tissue, defined as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs), which can reconstruct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation. The microenvironment that CSCs depend on consists of various cellular components and corresponding medium components. Among these factors existing at a variety of levels and forms, cytokine networks and numero ...[more]

PMID: 38292177

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Project description:BACKGROUND:Tumor hypoxia is an independent prognostic factor associated with poor patient survival. Emerging evidence suggests that hypoxia can potentially maintain or enhance the stem cell phenotype of both normal stem cells and cancer cells. However, it remains to be determined whether cell fate is regulated in vivo by the hypoxic tumor microenvironment (TME). METHODS:We established a hypoxia-sensing xenograft model to identify hypoxic tumor cell in vivo primarily using human breast cancer cell lines MDA-MB-231 and MCF7. Hypoxic tumor cells were identified in situ by fluorescence of green fluorescence protein. They were further isolated from xenografts, purified and sorted by flow cytometry for detailed analysis of their stem cell characteristics. RESULTS:We have found that hypoxic tumor cells freshly isolated from xenografts contain increased subpopulations of tumor cells with cancer stem cell (CSC)-like characteristics. The CSC characteristics of the hypoxic tumor cells are further enhanced upon re-implantation in vivo, whereas secondary xenografts derived from the non-hypoxic tumor cells remain similar to the primary xenografts. Interestingly, the phenotypes exhibited by the hypoxic tumor cells are stable and remain distinctively different from those of the non-hypoxic tumor cells isolated from the same tumor mass even when they are maintained under the same ambient culture conditions. Mechanistically, the PI3K/AKT pathway is strongly potentiated in the hypoxic tumor cells and is required to maintain the CSC-like phenotype. Importantly, the differential cell fates between hypoxic and non-hypoxic tumor cells are only found in tumor cells isolated from the hypoxic TME in vivo and are not seen in tumor cells treated by hypoxia in vitro alone. CONCLUSIONS:These previously unknown observations suggest that the hypoxic TME may promote malignant progression and therapy resistance by coordinating induction, selection and/or preferential maintenance of the CSC-like phenotype in tumor cells.

Project description:The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.

Dataset Information

Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting.

Publications

Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting.

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