Trends in Cell Biology
Feature ReviewSpecial Issue: Cell Biology of CancerMicroenvironmental regulation of therapeutic response in cancer
Section snippets
The TME orchestrates tumorigenesis and malignant progression
While cancer was long considered a disease defined and driven by genomic instability, chromosomal alterations, and genetic mutations [1], the influence of nonmalignant, stromal cells of the TME is now widely appreciated 2, 3. Tumors are complex tissues comprising not only malignant cells but also genetically stable stromal cells [4], including endothelial cells, fibroblasts, and immune cells among many others (Figure 1), in addition to the extracellular matrix (ECM) they produce. As in healthy
Therapeutic response is significantly influenced by the TME
Although an increasing number of cancers can be treated successfully if detected at an early stage, the presence of disseminated disease or recurrence of the primary tumor still confer a poor patient prognosis 6, 7. This is due in part to the current paucity of effective therapeutic options in this setting [8]. An initial response to treatment is often followed by disease progression, which, accompanied by a diminution of therapeutic options, ultimately leads to treatment failure and death from
Effects of pre-existing TME properties on therapeutic efficacy
The intrinsic mechanisms through which the TME modulates drug response involve pre-existing properties of the tumor including a chaotic, frequently inefficient vascular supply, elevated interstitial fluid pressure (IFP), a pronounced desmoplastic stroma, increased tissue rigidity, and the presence of niches within the tumor that protect cancer cells from therapeutic insults. As several of these parameters have been previously reviewed 24, 25, 26, 27, 28, we only briefly summarize these topics
Therapy-induced responses and acquired resistance in the TME
In the previous section we discussed intrinsic, pre-existing niches and the physical properties of the TME that contribute to non-cell-autonomous therapeutic resistance. Here we focus on how the TME can also be significantly changed by therapeutic intervention and how this can lead to acquired resistance (Figure 2). One paradigmatic example of TME alterations following therapy involves the response of the innate and adaptive immune system.
Concluding remarks
The number of mechanisms by which cancers can develop resistance to various therapeutic interventions inevitably increases as our arsenal of anticancer treatments expands. We can clearly now add TME-mediated resistance to this list and, as indicated by the representative examples we have highlighted here, and by emerging areas of interest (Box 4), these mechanisms of resistance are similarly diverse in their nature. While there are an increasing number of TME-targeted approaches to circumvent
Acknowledgments
The authors apologize to researchers whose work is not cited due to space limitations. They thank Oakley Olson and Daniela Quail for critical reviews of the manuscript. Research in the Joyce laboratory is supported by the National Institutes of Health (CA181355, CA148967), the American Cancer Society (RSG-12-076-01-LIB), and the Breast Cancer Research Foundation. F.K. is supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (KL 2491/1-1).
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