Tracing the path

Inflammation is something of a problem child within the human immune system. In normal cases, inflammation is the result of the immune system targeting biologic invaders—germs, viruses, etc.—but if the inflammatory response isn't shut off once the threat is dealt with, it can lead to chronic inflammation, which triggers more problems. Some of the conditions linked to chronic inflammation include asthma, rheumatoid arthritis, lupus, heart disease, Crohn's disease and even cancer.

That last contender, and its connection with inflammation, is the subject of recent research from the Chinese Academy of Sciences.

Inflammatory microenvironments have been found to play roles in carcinogenesis, cancer development and metastasis, but the exact mechanisms by which this occurs have remained elusive, as noted in a Chinese Academy of Sciences press release. Prof. Jing-Dong Jackie HAN from CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health of Chinese Academy of Sciences led a research team that sought to suss out those mechanisms. Their work was published in Cell Reports on Feb. 12, in a paper titled “Immune Cell Types and Secreted Factors Contributing to Inflammation-to-Cancer Transition and Immune Therapy Response.”

The scientists developed a computational network analysis package that they named “SwitchDetector,” which was used to integrate expression profiles from normal tissues and tissues with inflammation—namely, samples from liver, esophageal and colon cancers. Their work revealed that angiogenesis—the formation of new blood cells—is a common event in the inflammation-to-cancer (I2C) transition in several cancer types.

"Many studies have been carried out to tackle this challenge, and it has been found that cytokines and other soluble factors secreted by infiltrating immune cells can reprogram local cells in inflamed tissue microenvironments and are thus the focus of most biomarker studies (Grivennikov et al., 2010, Landskron et al., 2014, Lu et al., 2006),” the authors explained in their paper. “Secreted factors, such as cytokines and chemokines, are positively and negatively involved in cell transformation and malignancy (Landskron et al., 2014); many are strongly associated with cancer development, and some are used in cancer diagnosis and prognosis (Prasad and McCullough, 2013, Shaw et al., 2014, Yoo et al., 2009), such as IL-6, IL-4, and IL-8 (Culig, 2011), while others have even been used in cancer therapies (Dranoff, 2004, Lee and Margolin, 2011). One role of secreted factors is to regulate angiogenesis, such as with VEGF, IL-1, and IL-13 that promote angiogenesis, while others such as IL-10 and TIMP1 inhibit it (Coussens et al., 2013, Nishida et al., 2006). Angiogenesis ensures the supply of oxygen and nutrients for cancer cells and plays critical roles in cancer initiation and development.”

Since tumor microenvironments are hypoxic, or low-oxygen, they need to establish additional sources of blood flow for more oxygen, which leads them to send out their own blood vessels. These vessels are often leaky, which is a main route by which cancer cells can travel from the tumor to distant tissues.

Using their SwitchDetector approach, the researchers found “protein-protein interactomes and gene expression signatures of different immune cells” as well as “interface genes between normal, inflammation, and cancer backgrounds and inferred regulatory immune cell types and their activated or repressed secreted factors and cytokine receptors (SFCRs) at the inflammation-to-cancer (I2C) transition.” In addition, according to the Cell Reports paper, they found “a transition stage between advanced inflammation and early cancerous transformation stages that not only governs the transformation process but also provides pre-cancer cellular and molecular markers and prognosis and immune therapy response predictors.”

In looking at their data from esophageal fibroblasts, the authors explained that they “identified a cytokine-related gene, TIMP1, and three angiogenesis-related genes, MMP2, MMP14, and HIF1A. TIMP1 is a glycoprotein and highly inducible by many cytokines (Ries, 2014). TIMP1 has cytokine-like activities and influences cell growth, apoptosis, differentiation, angiogenesis, and oncogenesis (Ries, 2014). MMP2 and MMP14 play an indirect role in angiogenesis by promoting VEGF mobilization and generating antiangiogenic factors (Mook et al., 2004). HIF1A is involved in initiating angiogenesis and promoting tumor growth. Additionally, TIMP1 is known to inhibit MMP proteins (Ries, 2014), and silencing the HIF1α gene can effectively inhibit hypoxia-induced upregulation of TIMP1.”

“We … found 21 SFCRs associated with 4 immune cell types (Figure 3D) that significantly predicted the expression of two key I2C interface angiogenesis genes, FLT1 and COL4A3, which peak right before, or at, the I2C transition (Figure 3D). The combinations of these genes better predicted cancer prognosis than single angiogenesis genes. Furthermore, in cancers that emerge from inflammation, as few as 2 of these 23 genes could predict immune therapy response with 89.3% accuracy, and 8 could predict with 92.9% accuracy,” the authors added.

Given their results, the researchers concluded, their results and approach represent a new tactic for identifying therapeutic targets in cancer and for predicting patient response to immune therapy. The team has made both their SwitchDetector package and the I2C database freely available to other researchers, and both can be accessed at www.inflammation2cancer.org.