Intervenolin suppresses gastric cancer cell growth through the induction of TSP‑1 secretion from fibroblast‑like stromal cells

Yoshida,Junjiro; Abe,Hikaru; Watanabe,Takumi; Kawada,Manabu

doi:10.3892/ol.2018.9485

Intervenolin suppresses gastric cancer cell growth through the induction of TSP‑1 secretion from fibroblast‑like stromal cells

Authors:
- Junjiro Yoshida
- Hikaru Abe
- Takumi Watanabe
- Manabu Kawada
View Affiliations

Affiliations: Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Research Foundation, Tokyo 141‑0021, Japan
Published online on: September 21, 2018 https://doi.org/10.3892/ol.2018.9485
Pages: 6777-6785

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Fibroblast‑like stromal cells modulate the growth of cancer cells, both positively and negatively. Growth modulation is achieved through the secretion of regulatory factors as well as by proteins within the extracellular matrix. Those cellular interactions present attractive targets for cancer chemotherapy. It was demonsrated a novel natural compound, intervenolin (ITV), inhibited the in vitro growth of human gastric cancer cells when co‑cultured with stromal cells. Importantly, the inhibition was enhanced by the presence of stromal cells. The present study reported a mechanism of ITV action. Human gastric fibroblast‑like stromal cells (Hs738) were treated with ITV. The resultant conditioned medium (ITV CM) inhibited the growth of human gastric cancer cells and suppressed the level of c‑Myc protein. This result suggested that ITV negatively modulated cancer cell growth by upregulating the secretion of factors originating from stromal cells in the co‑culture system. To better understand the mechanism, ITV CM was subjected to proteomic analysis. The data revealed that one of the candidate regulators was thrombospondin‑1 (TSP‑1). Recombinant human TSP‑1 protein inhibited the growth of gastric cancer cells. Moreover, the growth‑inhibitory activities of ITV CM as well as that of recombinant TSP‑1 were blocked by neutralizing antibody targeting TSP‑1. These results suggested that ITV inhibited the growth of gastric cancer cells through its modulation of stromal cell function.

View Figures

View References

1	Subramaniam KS, Tham ST, Mohamed Z, Woo YL, Adenan Mat NA and Chung I: Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. PLoS One. 8:e689232013. View Article : Google Scholar : PubMed/NCBI
2	Vermeulen L, De Sousa E, Melo F, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, et al: Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 12:468–476. 2010. View Article : Google Scholar : PubMed/NCBI
3	Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, et al: Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 19:257–272. 2011. View Article : Google Scholar : PubMed/NCBI
4	Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr HA, Delaloye JF and Huelsken J: Interactions between cancer stem cells and their niche govern metastatic colonization. Nature. 481:85–89. 2011. View Article : Google Scholar : PubMed/NCBI
5	Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, et al: Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 487:505–509. 2012. View Article : Google Scholar : PubMed/NCBI
6	Kumari N, Dwarakanath BS, Das A and Bhatt AN: Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 37:11553–11572. 2016. View Article : Google Scholar : PubMed/NCBI
7	Yin SY, Jian FY, Chen YH, Chien SC, Hsieh MC, Hsiao PW, Lee WH, Kuo YH and Yang N: Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis. Nat Commun. 7:113112016. View Article : Google Scholar : PubMed/NCBI
8	Kawada M, Inoue H, Usami I and Ikeda D: Phthoxazolin A inhibits prostate cancer growth by modulating tumor-stromal cell interactions. Cancer Sci. 100:150–157. 2009. View Article : Google Scholar : PubMed/NCBI
9	Kawada M, Inoue H, Ohba S, Masuda T, Momose I and Ikeda D: Leucinostatin A inhibits prostate cancer growth through reduction of insulin-like growth factor-I expression in prostate stromal cells. Int J Cancer. 126:810–818. 2010.PubMed/NCBI
10	Kawada M, Inoue H, Ohba S, Yoshida J, Masuda T, Yamasaki M, Usami I, Sakamoto S, Abe H, Watanabe T, et al: Stromal cells positively and negatively modulate the growth of cancer cells: Stimulation via the PGE2-TNFα-IL-6 pathway and inhibition via secreted GAPDH-E-cadherin interaction. PLoS One. 10:e01194152015. View Article : Google Scholar : PubMed/NCBI
11	Kawada M, Inoue H, Ohba S, Hatano M, Amemiya M, Hayashi C, Usami I, Abe H, Watanabe T, Kinoshita N, et al: Intervenolin, a new antitumor compound with anti-Helicobacter pylori activity, from Nocardia sp. Ml96-86F2. J Antibiot (Tokyo). 66:543–548. 2013. View Article : Google Scholar : PubMed/NCBI
12	Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J and Iruela-Arispe Ml: Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA. 98:12485–12490. 2001. View Article : Google Scholar : PubMed/NCBI
13	Kawada M, Masuda T, Ishizuka M and Takeuchi T: 15-Deoxyspergualin inhibits Akt kinase activation and phosphatidylcholine synthesis. J Biol Chem. 277:27765–27771. 2002. View Article : Google Scholar : PubMed/NCBI
14	Fukazawa H, Mizuno S and Uehara Y: A microplate assay for quantitation of anchorage-independent growth of transformed cells. Anal Biochem. 228:83–90. 1995. View Article : Google Scholar : PubMed/NCBI
15	Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak Ml, Nicolae A, Singh SP, Nie Z, Levens D, et al: Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors. Sci Rep. 3:16732013. View Article : Google Scholar : PubMed/NCBI
16	de Marval Miliani PL, Macias E, Rounbehler R, Sicinski P, Kiyokawa H, Johnson DG, Conti CJ and Rodriguez-Puebla Ml: Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues. Mol Cell Biol. 24:7538–7547. 2004. View Article : Google Scholar : PubMed/NCBI
17	Wu S, Yin X, Fang X, Zheng J, Li L, Liu X and Chu L: c-MYC responds to glucose deprivation in a cell-type-dependent manner. Cell Death Discov. 1:150572015. View Article : Google Scholar : PubMed/NCBI
18	Togo S, Polanska UM, Horimoto Y and Orimo A: Carcinoma-associated fibroblasts are a promising therapeutic target. Cancers. 5:149–169. 2013. View Article : Google Scholar : PubMed/NCBI
19	Rogers NM, Sharifi-Sanjani M, Yao M, Ghimire K, Bienes-Martinez R, Mutchler SM, Knupp HE, Baust J, Novelli EM, Ross M, et al: TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction. Cardiovasc Res. 113:15–29. 2017. View Article : Google Scholar : PubMed/NCBI
20	Schmidt EV: The role of c-myc in cellular growth control. Oncogene. 18:2988–2996. 1999. View Article : Google Scholar : PubMed/NCBI
21	Seliger C, Leukel P, Moeckel S, Jachnik B, Lottaz C, Kreutz M, Brawanski A, Proescholdt M, Bogdahn U, Bosserhoff AK, et al: Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro. PLoS One. 8:e789352013. View Article : Google Scholar : PubMed/NCBI
22	Albo D, Rothman VL, Roberts DD and Tuszynski GP: Tumour cell thrombospondin-1 regulates tumour cell adhesion and invasion through the urokinase plasminogen activator receptor. Br J Cancer. 83:298–306. 2000. View Article : Google Scholar : PubMed/NCBI
23	Hyder SM, Liang Y and Wu J: Estrogen regulation of thrombospondin-1 in human breast cancer cells. Int J Cancer. 125:1045–1053. 2009. View Article : Google Scholar : PubMed/NCBI
24	Yee KO, Connolly CM, Duquette M, Kazerounian S, Washington R and Lawler J: The effect of thrombospondin-1 on breast cancer metastasis. Breast Cancer Res Treat. 114:85–96. 2009. View Article : Google Scholar : PubMed/NCBI