Trends in Cell Biology
Volume 25, Issue 4, April 2015, Pages 198-213
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Feature Review
Special Issue: Cell Biology of Cancer
Microenvironmental regulation of therapeutic response in cancer

https://doi.org/10.1016/j.tcb.2014.11.006Get rights and content

Highlights

  • The TME significantly influences therapeutic response.

  • Contributions from the TME can both abrogate and enhance the efficacy of therapeutic interventions.

  • Both pre-existing and therapy-induced mechanisms are instrumental to this effect.

  • Re-educating the TME could help to increase therapeutic efficacy.

The tumor microenvironment (TME) not only plays a pivotal role during cancer progression and metastasis but also has profound effects on therapeutic efficacy. In the case of microenvironment-mediated resistance this can involve an intrinsic response, including the co-option of pre-existing structural elements and signaling networks, or an acquired response of the tumor stroma following the therapeutic insult. Alternatively, in other contexts, the TME has a multifaceted ability to enhance therapeutic efficacy. This review examines recent advances in our understanding of the contribution of the TME during cancer therapy and discusses key concepts that may be amenable to therapeutic intervention.

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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