By Kai Yee Eng
The immune system is undeniably one of the most complex systems in the human body, functioning to defend us against pathogens and any molecules which might harm our body. One of the key mechanisms of the immune system is inflammation. Through this process, white blood cells such as monocytes and lymphocytes are recruited to remove the threat from the site of infection. This tightly regulated process is crucial to initiate the healing process and maintain homeostasis.(Chen et al., 2018)
While inflammation plays an important role in fighting against pathogens, there is a close relationship between inflammation and cancer. This relates to the process of wound healing, which can be broken down into three main steps: inflammation, new tissue formation, and tissue remodelling. (Schäfer & Werner, 2008) The intense crosstalk between stromal cells and the microenvironment at the site of inflammation can induces metastasis. Some reviews even state that inflammation could be the 7th hallmark of cancer, due to the idea of cancer as a “never ending wound healing process”.(Liu, Lin & Zhou, 2015; Schäfer & Werner, 2008)
The interaction between cancer cells and inflammation is complex, and therefore only three of the key mediators involved in inflammation and metastasis are introduced here. These are: tumour-associated macrophages (TAMs), cancer-associated fibroblast (CAFs) and myeloid-derived suppressor cells (MDSCs). (Liu, Lin & Zhou, 2015)
Myeloid-derived suppressor cells (MDSCs) are cells derived from bone marrow. It is suggested that they mediate their role in metastasis via two pathways. The first pathway focuses on the production of metalloproteinases (MMPS). (Ye, Yu & Bian, 2010) MMPs are a key protein in tissue remodelling as they play a major role in breaking down matrix protein. For example, MMP-9, which is largely produced by MDSCs, breakdowns type IV collagen, and leads to extracellular matrix (ECM) degradation. This promotes cell migration and facilitate the extravasation or intravasation, through breakdown of structural molecules in blood vessels. (Fleming et al., 2018) Furthermore, MMP-9 secretion also promotes neovascularisation to enhance the bioavailability of vascular epithelial growth factor (VEGF).(Condamine et al., 2015)
MDSCs secrete chemoattractant to create a premetastatic niche. (Ye, Yu & Bian, 2010) This process aims to achieve immunosuppression to increase the tumour cell survivability at the secondary site of growth, suppressing the activity of natural killer cells, a cytotoxic lymphocyte which are capable to kill cancer cells. (Safarzadeh et al., 2018) MDSCs produce chemoattractants S100A8 and S100A9 when induced by VEGF-A, TGFβ and TNFα. TGFβ can be produced by MDSCs itself in a premetastatic niche and this forms a positive loop feedback to increase the production of S100A8 and S100A9. (Srikrishna, 2011; Condamine et al., 2015) S100A8 can induce the stimulation of NF-κB which is important for tumour formation. Researchers had also shown that melanoma cells are preferentially migrated in mouse model under the action of S100A8 and S100A9.(Saha et al., 2010) Once they have reached the premetastatic niche, MDSCs can even recruit more MDSCs after inducing serum amyloid A through S100A8/S100A9. (Condamine et al., 2015)
Fibroblasts are involved in wound healing, during which they synthesize extracellular matrix, reform collagen and remodel the tissue at the site of injury.(Bainbridge, 2013) In the context of tumour cells, cancer-associated fibroblasts (CAFs) respond to the inflammation and tissue damage in a similar way: they transdifferentiate to myofibroblasts. CAFs recruited by TGF-β1 and PDGF (which is stimulated over a prolonged period by the cancer cells) induces desmoplasia, the growth of connective tissue. (Karagiannis et al., 2012). As fibroblasts are constantly receiving signals to transdifferentiate, the process is always active. It was also observed that the fibroblasts replaced the stromal cells with high density collagenous structure, which is identical to the wound healing process.
CAFs is also involved in regulation other pathways involved in cancer progression and metastasis. The Jak/STAT3 is one of the pathways regulated by IL-6 secreted by CAFs. (Kwa, Herum & Brakebusch, 2019). This pathway is crucial as it leads to increase metastatic ability via increased activity of epithelial and mesenchymal transition. (Jin, 2020) Additionally, it has been shown that the IL-6/STAT 3/NOTCH signalling pathway can increase stem-cell like properties in liver carcinoma and enhance the potential of tumour metastasis and progression.(Xiong et al., 2018) CAFs also produce Wnt ligands to activate the Wnt/β-catenin pathway, which is a well-known pathway involved in the cell proliferation(Jung & Park, 2020)
Differentiated from monocytes, tumour-associated macrophages (TAMs) are formed from signals from the microenvironment of the tumour site. TAMs can be both pro-inflammatory (M1 macrophages) and anti-inflammatory (M2 macrophages) depending on the tumour environment. TAMs are well-known for their production of inflammatory factor TNF-α and of MMPs. (Yang et al., 2020) TNF-α upregulates transcription factor Snail to inhibit expression of E-cadherin, a key protein in cell-cell junction formation. MMPs, on the other hand, are involved in the breakdown of ECM.
Co-culture of TAMs and ovarian cancer cell line have demonstrated that macrophages are involved in the regulation of c-Jun N-terminal kinase and nuclear factor kappa B (NF-κB) signaling pathways. (Hagemann et al., 2005) This former can regulate the mitogen-activated protein kinases (MAPK) signalling pathway to interfere with biological processes such as cell death and proliferation. (Dou et al., 2019) NF-κB is an important regulator, and its accumulation leads to recruitment of pro-inflammatory cytokines, creating a favourable environment for the growth of tumour.(Xia, Shen & Verma, 2014) Lastly, NF-κB can increases the cell survival by activating anti-apoptotic genes such as caspase-8 inhibitor FLIP, as well as inhibiting expression of apoptotic genes in the Bcl family.(Xia, Shen & Verma, 2014)
It is clear that inflammation has a strong relationship with cancer metastasis via cells involved in these processes. However, the description above has been greatly simplified. The communication between inflammation, cancer cells and the microenvironment is highly dynamic and complicated. With this, anti-inflammatory drugs such as NSAIDs have been developed. (Rayburn, Ezell & Zhang, 2009) These drugs not only aim to reduce the inflammation but can also provide chemoprotective effect against chemotherapy. Therefore, there is a huge potential in exploring the effect of anti-inflammatory drugs – which are already approved by the FDA – in cancer therapy or cancer prevention.
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