Curcumin quiets crosstalk in tumor cellular environment

Curcumin quiets crosstalk in tumor cellular environment

Life Extension Update

Tuesday, October 7, 2014. The journal PLOS One published an article on September 19 demonstrating BCM-95® curcumin altered the microenvironment of a colorectal cancer cell culture model, thereby reducing tumor promoting factors and potentially enhancing chemotherapy effectiveness.

"Accumulating evidence suggests that the development and progression of colorectal cancer is due to genetic and epigenetic alterations that are the result of complex interactions of transformed cells with their microenvironment," explain authors Constanze Buhrmann of Ludwig Maximilian University in Germany and her colleagues. "The tumor microenvironment is regarded as the tumor bed, which comprises of resident components, such as stromal cells and the factors that are stable within the milieu of the stroma, and nonresident components such as different immune cell populations, which influence tumor invasion and metastasis. The synergistic impact of the microenvironment on inflammatory responses and tumor progression is now considered to be an essential feature of carcinogenesis, and there is growing interest in the identification of agents that specifically target the pathway interaction between the tumor and stromal cells."

Dr Buhrmann and associates cultured human colon cancer cells with human stromal fibroblast cells for three days. They observed clustering of the cancer cells around the stromal cells, which established close cell-to-cell contact. This cellular interaction was associated with increased expression of adhesion and metastatic molecules, active cell cycle proteins, transforming growth factor-beta3 (TGF-beta3) and vimentin, which is a marker of epithelial to mesenchymal transition (EMT), a process that supports the initiation of metastasis.

The team then employed a three dimensional high density tumor microenvironment in which colon cancer cells were co-cultured with stromal cells and treated with varying concentrations of BCM-95® curcumin and/or the chemotherapeutic drug 5-fluorouracil (5-FU). While 5-FU alone increased tumor-promoting factors, TGF-beta3, and EMT, pretreatment with curcumin prior to 5-FU administration reduced these factors. Treatment with 5-FU and/or curcumin promoted disintegration of high-density tumor spheres, an effect that was greater in curcumin-treated co-cultures.

Cancer stem cells, which are believed to be responsible for treatment resistance and tumor recurrence, were more numerous in co-cultured cancer and stromal cells in comparison with cancer cells alone, indicating the role of crosstalk in supporting in tumor promotion. Administration of curcumin with or without 5-FU inhibited and diminished the expression of cancer stem cell markers, while 5-FU alone was associated with an increase—a fact that the authors attribute to a defense reaction of the tumor cell culture and microenvironment.

The results, according to the authors, demonstrate "for the first time, the modulating effect of curcumin on the crosstalk between the colorectal cancer cells/cancer stem cells and the fibroblasts in the tumor microenvironment, creating an adequate climate for more effective chemotherapeutic action of 5-FU to specifically target chemoresistant colorectal cancer cells."

They conclude "that the natural NF-kB inhibitor curcumin is a promising modulator of the synergistic crosstalk in the tumor microenvironment and curcumin-based anti-EMT and tumor progression may be a promising therapeutic strategy to prevent resistance to chemotherapeutic agents, sensitizing cancer stem cells to 5-FU and impede metastasis."

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Curcumin may help prevent metastasis
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Writing in an article published online on October 5, 2012 in the journal Carcinogenesis, German and Italian researchers report an anti-metastatic effect for curcumin, a compound that occurs in the spice turmeric, in an animal model of prostate cancer.

Previous experimentation by the team uncovered an inhibitory effect for curcumin against the expression of pro-inflammatory immunomodulator cytokines that include CXCL1 and CXCL2, which are associated with breast cancer metastases. The current research found a similar inhibitory action for curcumin in prostate carcinoma cells via inhibition of nuclear factor kappa-beta (NFκB). Upon testing curcumin in a mouse model of prostate cancer, a significant decrease in lung metastases was observed.

"Chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive pro-inflammatory and pro-metastatic feedback loop between NFκB and CXCL1/-2," the authors write. "Curcumin disrupts this feedback loop by the inhibition of NFκB signaling leading to reduced metastasis formation in vivo."

"Due to the action of curcumin, the tumor cells synthesize smaller amounts of cytokines that promote metastasis," commented lead researcher Beatrice Bachmeier of Ludwig-Maximilians-University Munich. "As a consequence, the frequency of metastasis formation in the lungs is significantly reduced, in animals with breast cancer, as we showed previously, or carcinoma of the prostate, as demonstrated in our new study."

"This does not mean that the compound should be seen as a replacement for conventional therapies," she added. "However, it could play a positive role in primary prevention – before a full-blown tumor arises – or help to avert formation of metastases. In this context the fact that the substance is well tolerated is very important, because one can safely recommend it to individuals who have an increased tumor risk."

Dr Bachmeier is planning a clinical trial to evaluate the effects of curcumin in treatment-resistant prostate cancer patients.

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Health Concern

Colorectal cancer

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Colorectal cancer remains the second most common cause of cancer death in the United States, although as much as 70% of cases are thought to be preventable through moderate dietary and lifestyle modifications (Anand 2008; Thompson 2011).

The colorectal cancer mortality rate has consistently declined in recent decades due largely to enhanced accuracy of early detection techniques, such as colonoscopy. However, the outlook for colon cancer patients rapidly diminishes if the cancer has metastasized to other organs or lymph nodes before detection.

People with chronic inflammatory conditions of the bowel, such as Crohn's disease or ulcerative colitis (UC), have up to a six times greater risk of developing colon cancer than those without the conditions (Mattar 2011). However, the inflammatory process is involved in the development of colorectal cancer growths even in those without Crohn's or ulcerative colitis (Rhodes 2002; Terzic 2010).

NF-Kappa B (NF-kB), a proinflammatory mediator that influences more than 500 genes involved in proliferation, angiogenesis, immune evasion and metastatic spread, has been the topic of intense research. Not surprisingly, NF-kB is a target for thwarting cancer's growth and many natural agents act on NF-kB to prevent its signaling. The most notable natural agent able to suppress NF-kB signal transmission is curcumin (Gupta 2011). The high intake of curcumin, and resultant inhibition of NF-kB, may be one reason that the incidence of colon cancer in India is so much lower than in the US or Europe (Aggarwal 2009).

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