A little more background...

Hey guys! Welcome back to my blog – I’m really glad you’re here! Today is going to be more of a info day, with a lot more research about the topics involved in my project! Wear your seatbelts, cuz it’s going to be a hectic flight off to the world of cancer biology!

(apologies for the really bad jokes – my sense of humor is broken :))

Lung cancer is the second most common type of cancer in both males and females in the United States. About 80-85% is diagnosed as non-small cell lung cancer (NSCLC) and about 10-15% of lung cancers are diagnosed as small cell lung cancer (SCLC). There has been a lot of research as to how we can cure cancer, and one such field in the modern day is immunotherapy. Immunotherapy is focused on boosting parts of the immune system in order to find and destroy cancer cells, and thus has been termed to be more precise than other cancer therapies, with less side effects.

Unfortunately, many of the current cancer therapies aren’t very effective at treating late stage lung cancer, which is when most people get diagnosed. Many medications are extremely expensive, meaning that many times people cannot afford to get the treatment they need. With my project, I hope to find a novel potential treatment for non-small cell lung cancer that is also cheaper for people to use. This experiment can help increase the effectiveness of immunotherapy treatment in lung cancer by combining two natural compounds, curcumin and quercetin that have been known for their immune modulatory effects. To test my hypotheses, I will be using dose-response cytotoxicity/migration assays that are useful in measuring cell migration and invasion, especially for cancer cells. 

Immune cells consist of T cells, B cells, Natural Killer cells (NK), macrophages (M1 and M2), stromal cells, endothelial cells, and cancer-associated fibroblasts that all function to suppress or promote tumor growth. T cells develop a T-cell receptor that recognizes specific antigens on a tumor cell and consequently kills the tumor cell, putting a halt to angiogenesis, which is the formation of new blood vessels. Angiogenesis is the process that produces all capillaries, and is regulated by a number of substances, including endostatin, adhesion molecules, and growth factors. Dysregulated angiogenesis contributes to tumor growth and metastasis. Tumor angiogenesis depends on interactions between tumor cells and endothelial cells, and VEGF, a signaling protein that promotes the formation of new blood cells plays an important role in the growth and survival of endothelial cells, which are important in cell proliferation and tumor angiogenesis. However, T-cells can also become immune infiltrated and dysfunctional. B cells are responsible for antibody production, antigen presentation, and secretion of cytokines. Furthermore, lymphocytes are made up of both T and B cells where tumor infiltrating lymphocytes (TILs) play a significant role in research. TILs kill tumor cells but are more likely to be recruited by the tumor microenvironment (TME) and cause dysfunction in an immune response. The regulatory T cells (Tregs) act to suppress immune responses to maintain homeostasis, which can be very dangerous once recruited to the TME as they inhibit the formation of T cells. Recruitment to the TME means that the regular functions of the immune system that worked for the body now works in favor of the TME. Already existing immune cell mechanisms now promote TME growth as opposed to inhibiting it. This is one of the biggest problems that many immunotherapeutic treatments aim to solve. The immune system is the natural defense mechanism that the human body uses to combat diseases​, mainly using T-cells – which are one of the biggest targets of immunotherapy.

Quercetin and curcumin are both natural compounds that have immune modulatory effects, and thus are currently being explored as potential treatment options in immunotherapy. Quercetin has an anti-angiogenesis, anti-metastasis, and anti-proliferation effect on cancer cells. Quercetin has an anti-tumor effect by reducing development of blood vessels. Tumor angiogenesis and metastasis are caused by the interaction of VEGF and VEGF receptor 2 (VEGFR2). In addition, this natural component decreases tumor growth through targeting the VEGFR-2-mediated angiogenesis pathway and suppressing the downstream regulatory component AKT. Quercetin can also decrease cancer metastasis by suppressing various molecular pathways and angiogenesis. For example, in metastasis and progression of melanoma, the activation of c-Met receptor tyrosine kinase is important. Quercetin showed anti-metastatic activity in melanoma by inhibiting c-Met phosphorylation, reducing its homodimerization, and ultimately suppressing the HGF/c-Met signaling pathway. Additionally, quercetin also exhibits anti-proliferation effects on cancer cells. The p53 protein, as a tumor suppressor, plays an important role in preventing cancer by regulating the cell cycle, apoptosis, and DNA repair. Quercetin can induce cell cycle arrest and apoptosis in hepatocellular carcinoma cells (HCC) by stabilizing or inducing p53. Aurora B, a collection of kinases, is a member of the Aurora kinases family and plays a critical role in chromosomal alignment and segregation, and the inhibition of aurora B kinase resulted in cell-cycle arrest or even death. However, quercetin effectively suppresses anchorage-independent cell growth of lung cancer cells with highly expressed aurora B levels, and suppressed tumor growth of A549 cells by inhibiting aurora B. Quercetin also has a regulatory effect on immune cells and promotes the proliferation of γδ T cells and the differentiation of γδ T cells into Vδ2 T cells, which strengthens their antitumor ability.

Curcumin is the other natural compound that has been shown to have immunotherapeutic effects. Curcumin, extracted from ginger, has been shown to effectively inhibit tumor growth, proliferation, invasion, metastasis and angiogenesis in tumors, and can modulate the tumor immune response and the tumor microenvironment. Immune dysfunction usually happens during tumor progression and contributes to tumor immune evasion. CD8+ cytotoxic T lymphocytes (CTLs) are involved in antigen-specific tumor destruction and CD4+ T cells are essential for helping this CD8+ T cell-dependent tumor removal. Tumors often target and inhibit T-cell function to escape from the immune system, which causes the loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells. 

Tumor cells induce apoptosis, which is induced cell death, of T cells by interfering with the production of NF-κB in T cells, making T cells susceptible to TNF-α-mediated apoptosis. Curcumin neutralizes oxidative stress of tumor cells, restores NF-κB activity and reactivates the TNF-α signal pathway, thereby enhancing the ability of T cells to resist apoptosis. It prevents this loss of T cells, expanded central memory T cell (TCM)/effector memory T cell (TEM) populations, reversed the type 2 immune bias and prevented the tumor-induced inhibition of T-cell proliferation in tumor-bearing hosts. Tumors also upregulates Treg cell populations and stimulates the production of the immunosuppressive cytokines transforming growth factor (TGF)-β and IL-10 in these cells. Curcumin inhibits this suppressive activity of Treg cells by downregulating the production of TGF-β and IL-10 in these cells. 

More importantly, curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Curcumin has also been shown to modulate signaling pathways involving Janus kinase (JAK)/signal transducers and activators of transcription (STAT), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), Wnt/β-catenin, vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) and genes such as cyclin D1, TP53, BAX, BCL-2, hTERT and MMPs, which modulate the proliferation, migration and invasion, cell cycle and cell apoptosis of tumor cells. In addition, curcumin is a good method to decrease levels of tumor growth factors, like tumor growth-factor β1, which is involved in the epithelial-mesenchymal transition in tumor cells. 

In essence, by combining curcumin and quercetin to form a new combination therapy against non-small cell lung cancer, I hope to find an effective treatment against its migration and invasion capacity. Combining curcumin and quercetin can effectively block more pathways that cancer cells use to spread, which is incredibly important in the study of immunotherapy and cancer prevention.

Welp, that brings us to the end of today’s blurb. I hope you enjoyed reading, and hopefully it wasn’t too much of an info overload! Hope to see you next time!