Cancers develop in complex tissue environments, which they depend upon for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable, and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that reeducation of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here, we will discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, and recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves ratelimiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.A variety of stromal cells in the surrounding environment are recruited to tumours, and these not only enhance growth of the primary cancer but also facilitate its metastatic dissemination to distant organs. Cancer cells in an aggressive primary mass are adept at exploiting that particular tissue microenvironment; however, once they leave these favourable surroundings, they must possess traits that will allow them to survive in new environments. In order for a metastasis to occur, the intravasated cancer cell must survive in the circulation, arrive at the target organ (seeding), extravasate into the parenchyma and show persistent growth 1 . Each of these stages is inefficient and some are rate limiting 1,2 . For example, senescence or apoptosis of cancer cells at the stage of entry into the metastatic site prevents the spread of the majority of circulating cells [2][3][4] . Seeding can occur to multiple organs, but metastatic tumours may grow in only one or a few 5 . There is also increasing evidence that in some cases cancer cells can lie dormant for many years, and that seeding may occur several years before diagnosis of the primary tumour [6][7][8][9][10] . In another phenomenon, termed angiogenic dormancy, there is a balance of proliferation and apoptosis that results in micrometastases that do not progress further 11,12 . The microenvironment clearly suppresses NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the malignancy of these potentially metastatic cells 10 , and their re-activation to form a clinically relevant metastasis probably occurs through perturbations in the microenvironment. Nevertheless, despite this evidence for early seeding and dormancy, tumour size and grade are the main predictors of metastasis, and this has been reinforced in recent studies in mouse models 13 and by gene expression analysis that linked large tumour size with metastasis-enhancing gene signatures 14 . It has been hypothesized that this may be due to metastatic re-seeding to primary tumours 15 . If this is the case, nothing is currently known about the underlying mechanisms. Successful metastatic outgrowth thus depends on the cumulative ability of cancer cells to appropriate distinct microenvironments at each step in the metastatic cascade: the primary tumour, systemic circulation and the final metastatic site. In this Review we discuss instruct...

Glioblastoma multiforme (GBM) comprises several molecular subtypes including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend upon colony stimulating factor (CSF)-1 for differentiation and survival. A CSF-1R inhibitor was used to target TAMs in a mouse proneural GBM model, which dramatically increased survival, and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors including GM-CSF and IFN-γ facilitated TAM survival in the context of CSF-1R inhibition. Alternatively activated/ M2 macrophage markers decreased in surviving TAMs, consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in proneural GBM patients. Our results identify TAMs as a promising therapeutic target for proneural gliomas, and establish the translational potential of CSF-1R inhibition for GBM.

Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific T cells be generated, but also that these T cells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy.

The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer. By developing a comprehensive understanding of the complex and interconnected microenvironmental landscape of brain malignancies we will greatly expand the range of therapeutic strategies available to target these deadly diseases.