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Using Microarrays to Interrogate Microenvironmental Impact on Cellular Phenotypes in Cancer
Published on: May 21, 2019
Molecular pathways: involving microenvironment damage responses in cancer therapy resistance
1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 91809, USA.
Abstract:
The armamentarium of therapeutics used to treat cancer patients relies heavily on ionizing radiation and chemotherapeutic drugs that severely damage DNA. Tumor cells' responses to such treatments are heavily influenced by their environment: Physical contacts with structural elements such as the extracellular matrix, associations with resident and transitory benign cells such as fibroblasts and leukocytes, and interactions with numerous soluble endocrine and paracrine-acting factors all modulate tumor-cell behavior. Of importance, this complex tumor microenvironment is not static and dynamically responds to a variety of stimuli. Here, we describe emerging data indicating that genotoxic cancer treatments activate highly conserved damage response programs in benign constituents of the tumor microenvironment. These damage signals, transmitted via master regulators such as NF-κB, culminate in a powerful and diverse secretory program that generates a proangiogenic, proinflammatory microenvironment. Constituents of this program include interleukin (IL)-6, IL-8, hepatocyte growth factor, amphiregulin, matrix metalloproteinases, and other factors that have been shown to promote adverse tumor-cell phenotypes, such as enhanced resistance to treatment and rapid tumor repopulation. A detailed understanding of these survival signals induced in the context of genotoxic stress provides a platform for developing combinatorial treatment strategies that take into account malignant cells, the tumor microenvironment, and the dynamics exerted by the treatment itself.
Insights
Genotoxic cancer treatments activate benign cells in the tumor microenvironment. These cells release factors promoting tumor growth and treatment resistance, impacting cancer therapy outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment Research
Background:
- Cancer therapies like radiation and chemotherapy damage DNA, influencing tumor cell behavior.
- The tumor microenvironment, comprising extracellular matrix, benign cells, and soluble factors, dynamically modulates tumor responses.
- Benign cells within the tumor microenvironment play a critical role in cancer progression and treatment response.
Purpose of the Study:
- To investigate how genotoxic cancer treatments affect benign cells within the tumor microenvironment.
- To elucidate the signaling pathways and secreted factors involved in the tumor microenvironment's response to DNA-damaging agents.
- To understand how these microenvironmental changes impact cancer cell phenotypes, such as treatment resistance and repopulation.
Main Methods:
- Review of emerging data on damage response programs in benign tumor microenvironment constituents.
- Analysis of signaling pathways, including nuclear factor kappa B (NF-κB).
- Identification of key secreted factors (e.g., IL-6, IL-8, HGF) and their role in promoting pro-tumorigenic phenotypes.
Main Results:
- Genotoxic treatments activate conserved damage response programs in benign tumor microenvironment cells.
- These activated cells transmit damage signals via pathways like NF-κB.
- A proangiogenic and proinflammatory microenvironment is generated, characterized by factors promoting tumor cell resistance and repopulation.
Conclusions:
- Genotoxic stress in cancer treatment induces a pro-tumorigenic response from the tumor microenvironment.
- Understanding these microenvironment-mediated survival signals is crucial for developing effective combinatorial cancer therapies.
- Future strategies should consider the interplay between malignant cells, the tumor microenvironment, and treatment dynamics.
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