Tanaka M , Kuriyama S , Itoh G , Kohyama A , Iwabuchi Y , Shibata H , Yashiro M , Aiba N .

	Figure 1. Screening of chemicals that perturb gastrulation. (a) X‐Gal staining of a normal embryo after injection of nuclear‐localized β‐galactosidase mRNA into dorsal‐vegetal blastomeres at the eight‐cell stage. Cells stained blue are migrating mesodermal cells.44 (b) Vegetal or posterior‐dorsal views of stage 12–12 1/2 normal embryos (end of gastrulation). Arrows indicate blastopores. (d) Experimental sheme. (c, e, f) stage 12 1/2 embryos treated with 0.05% DMSO (control) or test chemicals (50 μM). (g) Stage 14 normal embryos (neurula stage). (h–k) Embryos at stage 14, treated with 0.05% DMSO (control) or test chemicals (50 μM). Bar = 2 mm.
	Figure 2. Screening of chemicals that perturb migration of cranial neural crest cells (CNCC). (a) Experimental scheme. (b) Migratory CNCC streams at the tailbud craniofacial area (stage 30). The blue region indicates CNCC. Arrows indicate the direction of migration. abr, anterior branchial arch; hy, hyoid segment; m, mandibular segment; Op, optic vesicle; Ot, otic vesicle; pbr, posterior branchial arch. (c, d) Whole‐mount in situ hybridization: FoxD3 is a pre‐migratory NCC marker and Dlx2 is a migratory NCC marker. Mixture of these probes indicates whole NCC. DMSO (0.1%) did not affect migratory patterns, which comprised four streams of cranial NCC. (c) Five chemicals induced severe defects in CNCC migration. (d) Three chemicals had relatively mild effects.
	Figure 3. 3D gel invasion assays. (a) Schematic showing the experiments in b–g. DiO‐labeled SAS cells and DiI‐labeled cancer‐associated fibroblasts (CAF) were mixed and placed onto the gel. (b–f) Representative photos of sectioned gels after 7 days of incubation. (h) Schematic representation of the experiments in i–l. CAF (DiI‐labeled, red) were embedded in gels in Transwells with 0.4‐μm pores; DiO‐labeled (green) SAS cells were then overlaid onto the gels. After incubation for 9 days, the gels were fixed and sectioned. (g, l) The invasion index was calculated and expressed as a ratio with respect to control cells treated with 0.005% DMSO. Results from three independent experiments are shown as means ± SD. *P < 0.05. Bar = 50 μm.
	Figure 4. C‐157 and D‐572 cause mitotic defect in SAS cells. (a) The structure of C‐157 and D‐572. (b–f) All experiments were observed at 15 h after addition of C‐157 and D‐572 (10 μM, each) or nocodazole (2 μM). (b) SAS cells were fixed with methanol and stained with α‐tubulin antibody (green). DNA was stained with DAPI (blue). Panels show spindle microtubules in control cells at metaphase and disrupted microtubules in drug‐treated cells at prometaphase. (c) Phase‐contrast microscope images in control and drug‐treated SAS cells. (d) Giemsa staining of control and drug‐treated SAS cells. After addition of each drug, cells were fixed with methanol/acetic acid and then stained by Giemsa solution. Arrows and arrowheads indicate the chromosome condensation and hyper‐condensation in mitotic phase, respectively. (e) Enlargement of interphase or mitotic cells in (d). (f) Frequency (%) of mitotic cells after C‐157 or D‐572 treatment. Mitotic cells were discriminated by the chromosome condensation as shown in (e) by Giemsa staining. *P < 0.05. (g) Live cell imaging of mitosis in SAS cells. Arrows in control cells indicate the daughter cells created by cell division. “Time 0” was defined as the onset of prophase.
	Figure 5. Effects of C‐157 and D‐572 on apoptosis and viability of SAS cells. (a, b) Apoptosis and viability of SAS cells after treatment with chemicals. The results from triplicate samples are shown as the means ± SD. (b, right panels) SAS cells were labeled with Hoechst 33342, and treated with chemicals. Arrows indicate representative apoptotic cells containing condensed or fragmented nucleus. (c) Western blot analysis of SAS cell lysates with antibodies against phosphorylated and total Erk and Akt. The intensity of each band was measured by ImageJ software and the relative ratio of phosphorylated‐to‐total Erk or Akt was calculated.
	Figure 6. Effects of C‐157 and D‐572 on tumor growth and invasion. (a) SAS cells were injected subcutaneously in nude mice and each compound (20 μM in 50 μL PBS) was injected three times at the same site as depicted. (b) Tumors were sectioned and subjected to HE staining. (c) Axcel cells were injected into the peritoneal cavity, followed by test chemicals (20 μM, 200 μL) as indicated. Arrow heads indicate disseminated tumors in the mesentery. The number of tumor nodules (>1 mm in diameter) in the mesentery was counted. (d) C6 cells were injected intra‐cranially into nude mice, and test compounds (20 μM, 20 μL) were injected as described in the text. Representative histology of the mouse cerebrum at 9 days post‐injection of tumor cells (H&E stain). T indicates the area occupied by tumor cells. (a–d) Five mice per each group were analyzed. Results are shown as means ± SD. *P < 0.05. Bar = 100 μm.

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