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Exploiting the Tumor Microenvironment for Cancer Therapeutics

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It’s more than a century since Paget first proposed the ‘soil and seed’ hypothesis in cancer, providing evidence that the environment surrounding a tumor is as important as the tumor itself.1 

Since that milestone, interest in the tumor microenvironment (TME) has waxed and waned. But after a landmark study in 2006 showed that immune cells, not tumor cells, are a better predictor of bowel cancer prognosis,2 research in this area has gathered momentum and it’s now the focus of intense research efforts.

What is the tumor microenvironment?

In addition to cancer cells, tumors are made up of a multitude of different cell types, which together comprise the tumor microenvironment. These include stromal cells, fibroblasts, endothelial cells that make up blood vessels within the tumor, the extracellular matrix and, perhaps of most interest right now, a multitude of different immune cells. Tumors influence their microenvironment through secreting growth factors, immune suppressive molecules and other signaling molecules that provide the perfect environment for a tumor to thrive.
That’s why understanding this microenvironment and finding new ways to disrupt it is such an important approach to cancer treatment.

Modeling the microenvironment

To better understand the influence of the many cellular players that make up a tumor, several labs are developing ways to image or model the TME, either to identify new drug targets, or as preclinical tools for drug development.

Dr Dan Gioeli of the University of Virginia Cancer Center, working with local biotech company HemoShear Therapeutics, is creating 3D models that mimic the microenvironment of pancreatic and non-small-cell lung cancers. The model aims to replicate the complex nature and behavior of a real tumor by incorporating different cell types that are found within them, such as vascular endothelial cells that are exposed to the tremendous shearing forces of blood flow.

"This model incorporates tumor hemodynamics and biological transport in a way that other tumor models do not," says Gioeli. “It enables us to understand the inner workings of tumors to systematically identify and test new ways to treat cancer."

Modeling metastasis

In another approach, Dr Andrew Wang and Dr Lola Reid from the University of North Carolina Lineberger Comprehensive Cancer Center have collaborated to engineer models of cancer metastases that reflect the microenvironment that promotes their growth.3 They generated ‘decellularized’ tissue, called biomatrix, derived from liver or lung tissue of rats, to coat petri dishes. They then used the petri dishes to grow bowel cancer cells, which preferentially metastasize to these target organs.

Their models build directly on Paget’s original theory and are intended to help scientists understand why cancers tend to spread to certain organs rather than others. “The hypothesis is this is caused by both 'seed and soil' - that the cancer cells have something in them that drive them to a particular organ, and the soil has to be right for them to grow,” sain Wang. “Our models will help us to better understand the conditions of the soil that help promote cancer metastasis."

A recent approach published in in the journal Biofabrication uses an interpenetrating hydrogel to develop a 3D model of a lung tumor in vitro. This work revealed novel insights about the process of epithelial-to-mesenchymal transition – an essential step in metastasis.4

These sophisticated models may just be the beginning however, as several other teams of researchers are fast pursuing ways to map an entire tumor in 3D and beyond.

At the National Physical Laboratory in London, Professor Josephine Bunch is leading a team developing a metabolic map of a tumor through cutting-edge multi-scale mass spectrometry methods. At the University of Cambridge, Professor Greg Hannon is exploiting the power of virtual reality to create an interactive, interrogatable map of breast tumors. Both teams answered Cancer Research UK’s 2015 Grand Challenge funding call to create a 3D map of a tumor.  

Targeting the tumor immune environment

The increased understanding of the TME from models such as these is essential for developing new cancer treatments. Especially so when it comes to understanding the importance of a tumor’s surrounding immune cells.

Maria Castro, Professor of Neurosurgery and Cell and Developmental Biology at the University of Michigan Medical School is testing a new treatment aimed at stimulating the immune microenvironment in brain tumors. It was the culmination of watching the relatively unexplored field of neuroimmunology over several years, she says.

“There was a prominent group in Oxford led by Professor Hugh Perry who did pioneering work on the immune system status in the brain, and another team in Vienna headed up by neuropathologist Professor Hans Lassman, who specialized in multiple sclerosis,” she recalls. “We studied their publications and spoke with them, and the consensus at that time was that due to the scarcity of cells that could kick-start an immune response from within the brain, it was not possible to elicit effective immune responses against brain cancers.” 

Targeting the tumor microenvironment: A two-pronged approach

This led Castro to think about ways to recruit these cells into the brain, and around the same time, a cytokine, FMS-like tyrosine kinase 3 ligand (FLT3L) was discovered that could do just that. “We thought, OK, if we can get this cytokine into the brain, it may do the trick.”

She combined her team’s expertise in gene therapy with the latest advances in immunotherapy, and the result was a two-pronged treatment approach that uses two recombinant adenoviral vectors, one encoding a conditional cytotoxic gene that kills actively dividing tumor cells and the other encoding the FLT3L cytokine that attracts immune antigen presenting cells.

“The combination of the two vectors enabled us to elicit shrinkage of a large tumor mass, and also create immunological memory”, she says. “This means once the primary tumor has shrunk and gone away, if the tumor returns, the immune cells are already primed to kill it”5.6

The treatment is now being tested in a Phase I trial in high grade glioma, and if the safety is successfully demonstrated, then they will open the trial to lower grade brain tumors which have a much better prognosis and also to pediatric brain tumor patients. 

Exploiting the tumor microenvironment to improve existing treatments

Over the past few decades, one of the key TME research focuses has been on blocking cancer’s blood supply using anti-angiogenic agents. While these may not have shown the promise in prolonging cancer survival that many had hoped for, they are having profound benefits on improving the quality of life for some patients, says Castro.

“In brain tumors the blood vessels become very leaky, and you have a lot of swelling which leads to severe side effects,” she explains. “There are patients who have to stop driving, can’t dress themselves and then you give them an anti-angiogenic medication, it normalizes the blood vessels and suddenly the brain function returns to normal. Thus, having a major impact in allowing these patients to have a more normal life for the remaining time.”

The TME may also be key to improving existing curative treatments. At Cold Spring Harbor Laboratory in the US, Assistant Professor Mikala Egeblad and her team used live imaging of tumors in mice to show that selective inhibition of matrix metalloproteinases (MMPs) and  CCR2 chemokines made breast tumors in mice more responsive to the drug, doxorubicin. This suggests it might be possible to engineer the TME to significantly improve the response of common cancers to existing "classical" chemotherapy drugs.7

From maps to models and modulating the immune microenvironment, it’s clear that research into the microenvironment is gaining momentum. The next generation of cancer treatments will not just take the TME into account, but are likely to involve combination approaches that target both the tumor and its surrounding support network.

1.  Paget, S. (1889) The distribution of secondary growths in cancer of the breast. Lancet 1, 571–573
2. Galon J, et al. (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313: 1960–1964.
3. Tian, X. et al. (2018) Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds. Nature Biomedical Engineering doi:10.1038/s41551-018-0231-0
4. Alonso-Nocelo, M. et al. (2018) Matrix stiffness and tumor-associated macrophages modulate epithelial to mesenchymal transition of human adenocarcinoma cells. Biofabrication 10 (3): 035004. doi: 10.1088/1758-5090/aaafbc.
5. Ali S, et al. (2005) Combined immuno-stimulation and conditional cytotoxic gene therapy provide long term survival in a large glioma model.  Cancer Research 6 5(16):7194-7204.  Portrayed in the Highlights section.  PMCID:  PMC1242178.
6. Curtin JF, et al. (2009) HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Medicine 6 (1):e10; PMCID: PMC2621261.
7. Nakasone, E. et al. (2012) Imaging Tumor-Stroma Interactions during Chemotherapy Reveals Contributions of the Microenvironment to Resistance. Cancer Cell 21 (4): 488-503