Paclitaxel (PTX) was widely used as a chemotherapy medication in the front line of several cancers, including ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer [1]. PTX could interfere with the normal function of microtubules in cell division, which was considered as the most effective and safe medicines on the World Health Organization's List of Essential Medicines [2-4].

Fig.1 Crystal structure of paclitaxel

     However, the latest research shown that although reducing tumor size, PTX increased the circulating tumor cells in the blood and enhanced the metastatic burden at the lung, which had been published on the PNAS by Prof. Hai [5]. The study revealed that there were two steps in the process. Firstly, PTX modulated the tumor microenvironment for metastasis at the microvasculature, to help cancer cells entering the blood stream. Then at the metastatic lung, PTX make cancer cells flourish in the tissue microenvironment. Notably, these changes had a great relationship with ATF3 [5].

Fig.2 PTX exacerbates breast cancer metastasis in a host-Atf3–dependent manner

Fig.3 A model showing how host-Atf3 and PTX affect multiple steps in the metastatic cascade at both the primary tumor site

      ATF3 was a member of the ATF/CREB family of transcription factors, which directly or indirectly altered the expression of a series of genes, and its target genes enabled to regulate inflammation as a key modulator of cancer progression [6-9]. As the metastatic burden in the WT-Ctl mice was significantly higher than that in the KO-Ctl group, host-Atf3 was indicated a prometastatic role. Importantly, knock-down Atf3 in the host would totally decrease the PTX to exacerbate metastasis. Through examining vessel density and analyses of gene expression, researchers found that Atf3 improved a proangiogenic microenvironment with PTX increasing the expressions of TMEM and CTCs, and TEM abundance would facilitate cancer cell invasion more efficiently. Then PTX stimulated lung colonization by cancer cells as the second site in a host-Atf3–dependent manner. After the metastasis, PTX also promoted the cancer cells to grow and to get rid of the cytotoxic program. Atf3 played a essential role for PTX to increase the chemokine (C-C motif) ligand 2, which was a key recruitment factor for monocytes, and acted importantly in cancer development [5].

Fig.4 Analyses of human cancer specimens

      For testing the consistence of the results between the human and mouse models, microarray datasets were used. The analyses of co-expression of ATF3 and TEK, which was the human ortholog of mouse Tie2, the expression of ATF3 positively with the CCL2 but negatively with the PRF1，as well as monocyte recruitment factors CCL7 and CCL8, cytotoxic immune cell marker CD8, various granzymes, and natural killer (NK) cell markers, indicated the research from mouse models had potential relevance to human cancer [5].

EIAab provides the kit for detecting the ATF3  http://www.eiaab.com/entries/detail/ATF3_HUMAN or please enter in www.eiaab.net for details. 

Reference

1. ^a b c d "Paclitaxel".The American Society of Health-System Pharmacists. Retrieved January 2, 2015.
2. Fischer, Janos; Ganellin, C. Robin. Analogue-based Drug Discovery. John Wiley & Sons. 2006, p. 512.ISBN 9783527607495.
3. ^ Jump up to: ^a b c d "Taxol® (NSC 125973)". National Cancer Institute. Retrieved 14 February 2016. Wayback machine
4. WHO Model List of Essential Medicines (19th List)"(PDF). World Health Organization. April 2015. Retrieved8 December 2016
5. YS Chang, SP Jalgaonkar, JD Middleton, et al. Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis. Proceedings of the National Academy of Sciences, 2017:201700455.
6. T Hai, MG Hartman. The molecular biology and nomenclature of the ATF/CREB family of transcription factors: ATF proteins and homeostasis. Gene, 2001, 273:1–11.
7. M Montminy. Transcriptional regulation by cyclic AMP. Annu Rev Biochem, 1997, 66: 807–822.
8.  T Hai, CC Wolford, YS Chang. ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: Is modulation of inflammation a unifying component? Gene Expr, 2010, 15: 1–11
9.  F Balkwill, A Mantovani. Inflammation and cancer: Back to Virchow? Lancet, 2001, 357: 539–545.

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