Cancers develop in complex tissue environments, which they depend on 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 re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

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Microenvironmental regulation of tumor progression and metastasis.

Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.

/pdf/molecular-mechanisms-and-clinical-applications-of-2j04l9iq9q.pdf

Molecular mechanisms and clinical applications of angiogenesis

Matrix Metalloproteinases: Regulators of the Tumor Microenvironment

Macrophage Diversity Enhances Tumor Progression and Metastasis

Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment

https://research-repository.uwa.edu.au/files/1548937/11262_PID11262.pdf

HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and Invasion

The hypoxic response of tumors is dependent on their microenvironment

Glioblastoma multiforme (GBM) is one the most aggressive brain tumors due to the fast and invasive growth that is partly supported by the presence of extensive neovascularization. The matrix metalloproteinase MMP-2 has been associated with invasive and angiogenic properties in gliomas and is a marker of poor prognosis. Since MMP-2 is expressed in both tumor cells and endothelial cells in GBM, we generated genetically engineered MMP-2 knockout (MMP-2ko) GBM to examine the importance of the spatial expression of MMP-2 in tumor and/or normal host-derived cells. MMP-2-dependent effects appeared to be dose-dependent irrespective of its expression pattern. GBM completely devoid of MMP-2 exhibited markedly increased vascular density associated with vascular endothelial growth factor receptor 2 (VEGFR2) activation and enhanced vascular branching and sprouting. Surprisingly, despite the high vascular density, tumor cells were more prone to apoptosis, which led to prolonged survival of tumor-bearing mice, suggesting that the increased vascularity is not functional. Congruently, tumor vessels were poorly perfused, exhibited lower levels of VEGFR2, and did not undergo proper maturation because pericytes of MMP-2ko tumors were not activated and were less abundant. As a result of impaired and dysfunctional angiogenesis, MMP-2ko GBM became more invasive, predominantly by migrating along blood vessels into the brain parenchyma.

/pdf/matrix-metalloproteinase-2-regulates-vascular-patterning-and-2enj06mnsq.pdf

Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM.

Individuals bearing germ line mutations in the Von Hippel-Lindau (VHL) tumor suppressor gene are predisposed to the development of highly angiogenic tumors. This is correlated with an increased expression of the angiogenic factor vascular endothelial growth factor (VEGF) in these tumors, which is in part caused by elevated expression of the HIF-1 hypoxia inducible transcription factors. We created malignant astrocytes with genetic deletions of the VHL gene and implanted them in subcutaneous and intracranial sites; these sites are respectively vessel poor and vessel-rich tissues. When grown in a vessel poor site, VEGF expression in VHL null cells was important for both vascularization and tumor growth. However, when the same cells are grown in the vessel-rich intracranial environment, loss of VEGF expression reduces vascularization, but does not affect tumor growth. This indicates that antiangiogenic therapies for tumors that express high levels of angiogenic factors such as VEGF may vary in their efficacy, with potentially lowered effectiveness in sites, such as the brain, that are inherently vessel rich.

Loss of vascular endothelial growth factor expression reduces vascularization, but not growth, of tumors lacking the Von Hippel-Lindau tumor suppressor gene.

Hanqiu Song

Papers

HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and Invasion

The hypoxic response of tumors is dependent on their microenvironment

Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM.

Loss of vascular endothelial growth factor expression reduces vascularization, but not growth, of tumors lacking the Von Hippel-Lindau tumor suppressor gene.