Oncogenomics

Oncogene (2004) 23, 2576–2581. doi:10.1038/sj.onc.1207352 Published online 22 December 2003

MASL1, a candidate oncogene found in amplification at 8p23.1, is translocated in immunoblastic B-cell lymphoma cell line OCI-LY8

Hiroyuki Tagawa1, Sivasundram Karnan1, Yumiko Kasugai1, Sinobu Tuzuki1, Ritsuro Suzuki1, Yoshitaka Hosokawa1 and Masao Seto1

1Division of Molecular Medicine, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan

Correspondence: M Seto, E-mail: mseto@aichi-cc.jp

Received 30 June 2003; Revised 22 October 2003; Accepted 11 November 2003.

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Abstract

Genetic amplification at chromosome 8p23.1 has been reported in some solid tumors. Translocation of 8p23.1 has also been reported in hematological malignancies and head and neck squamous cell cancer. In an attempt to clarify whether this translocation is implicated in lymphomagenesis, we performed FISH analysis of the immunoblastic B-cell lymphoma cell line OCI-LY8, which has chromosome translocation at 8p23.1, with various BAC clones. We found split signals on BAC, RP11-18L2 where the MASL1 gene is located. This translocation was found to produce a chimeric transcript of MASL1 exon 1 with a cryptic exon from the genome region at 14q21. Our study indicates that MASL1 is not only a target gene for genomic amplification but also for chromosomal translocation. Since tumorigenic activity of the MASL1 has not been proven, its in vitro transforming activity was studied and in vivo nude mice assay were performed. Although no in vitro transforming activity was detected by focus formation, the in vivo tumorigenesis assay with nude mice showed that both MASL1 and chimeric MASL1 possess tumorigenic activity. This suggests that MASL1 is an important oncogene not only for solid tumors but also for hematologic malignancies.

Keywords:

MASL1, lymphoma, oncogene, 8p23, translocation, amplification

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Introduction

The chromosome 8p23.1 region has been reported to feature many genomic alterations in various cancers. Deletion of chromosome 8p22–23, detected by allelic imbalance, is a frequent event in many different types of malignant tumors (Emi et al., 1992; Knowles et al., 1993; Matsuyama et al., 1994; Pykett et al., 1994; Sunwoo et al., 1996). CGH analysis has also demonstrated that genomic loss of chromosome 8p23 occurs frequently in leukemic mantle cell lymphoma (Martinez-Climent et al., 2001). Amplification of 8p23 has been found in a few solid tumors such as malignant fibrous histiocytoma (Sakabe et al., 1999) and gastric cancer (Sakakura et al., 1999). Sakabe et al. (1999) found MASL1 gene (malignant fibrous histiocytoma-amplified sequences with leucine-rich tandem repeat-1) as a candidate oncogene from the genome amplification region at 8p23.1 of malignant fibrous histiocytoma. Translocation of 8p23 has been reported in NK/T-cell lymphoma (Wong et al., 2000), and head and neck squamous cell carcinoma (Jin et al., 2001). However, the breakpoint at 8p23 has not yet been identified. OCI-LY8 was established at the Ontario Cancer Institute (OCI) from immunoblastic B-cell lymphoma (Tweeddale et al., 1987) and is known to contain a translocation at 8p23.1. In this study, we performed FISH analysis at 8p23.1 to detect a breakpoint of OCI-LY8 using various BAC clones and found that MASL1 gene was involved in this translocation. We further demonstrated the oncogenic activity of MASL1 gene with nude mouse tumorigenic assay.

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Results

FISH analysis

FISH analysis was performed focusing on 8p23. 1, with various BAC clones aligned at this region (Figures 1a and b). In OCI-LY8, 8p23.1 and 14q21 were reciprocally translocated (Figures 1 and 2). Of special importance is that, BAC, RP11-18L2 (BAC18L2, Accession no. AC090567) showed split signals on both derivative 8 and derivative 14 (Figure 2b and c). BAC326E7 on 14q21 labeled with FITC had spitted and showed fusion signals with BAC18L2 (labeled with Rodamine) at both der(8)t(18qtel right arrow 18q21double colon14q32 right arrow 14q21double colon8p23.1 right arrow 8q24double colon3q27 right arrow 3qtel) and der(14)t(8;14)(p23.1;q21) (Figure 2c).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Schematic illustration of chromosome 8 and breakpoint map of 8p23.1 and 14q21 in OCI-LY8 cells. All clones described in this figure were confirmed the right orders and right positional relationship by dual color FISH. (a) Schematic illustration of chromosomes 8 and 14. (b) BAC contig. Centromere (cen) and telomere (tel) are indicated with arrows. Closed circles represent STS markers. (c) MASL1 exon–intron structure on BAC18L2. 14q21 element and LOC3308906 (Accession no. XM2922419), which were predicted by Genscan, on BAC 326E7. The light gray boxes indicate the open reading frame. Exons are based on a comparison of MASL1 cDNA and BAC18L2 sequences. Exon 1: 1–3001 bp, Exon 2: 3002–3125 bp, Exon 3: 3126–3159 bp. The arrows indicate the breakpoints at 8p23.1 and 14q21 in OCI-LY8. On BAC 326E7, the gray box indicates a predicted gene by Genscan, LOC3308906 (Accession no. XM2922419) and the striped box indicates the cryptic exon of chemeric MASL1 in OCI-LY8. (d) MASL1 cDNA. MASL1 open reading frame is 3159 bp and encoding 1052 amino-acid polypeptide. The open reading frame consists of three exons. 14q21 element sequence was introduced after exon 2 (nucleotide number 3002) in OCI-LY8 cells

Full figure and legend (88K)

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Patial karyotypes (G-banding) and FISH analysis focusing on 8p23.1 and 14q21. In OCI-LY8, 8p23.1 and 14q21 were translocated reciprocally. (a) Partial karyotypes (G-band) of chromosome 8 and chromosome 14 in OCI-LY8 cells. The four derivative chromosomes shown are represented: der(8)-1, der(8)t(18qtel right arrow 18q21double colon14q32 right arrow 14q21double colon8p23.1 right arrow 8q24double colon3q27 right arrow 3qtel); der(8)-2, der(8)t(8;17)(p11;q11); der(14)-1, der(14)(8;14)(p23.1;q21); der(14)-2, der(14)t(8;14)(q24;q32). (b) FISH analysis of OCI-LY8 cells with BAC18L2 at 8p23.1. The BAC was labeled with FITC and hybridized with the chromosome 8 painting probe labeled with spectrum orange. Arrows indicate split signals of BAC18L2 at der(8)-1 and der(14)-1. (c) Dual color FISH with BAC18L2 (8p23.1) and BAC326E7 (14q21). Red signals of Rodamine indicate BAC18L2 and green signals of FITC are of BAC326E7. The arrows indicate the fusion signals on der(8)-1 and der(14)-1. The signal of BAC18L2 was not detected on der(8)t(8;17)(p11;q11) possibly because of deletion. Normal signal of BAC326E7 is only seen on der(14)-2 and split signals are seen on both der(8)-1 and der(14)-1 because of reciprocal translocation at 14q21

Full figure and legend (380K)

BLAST search with BAC18L2 sequence showed that MASL1 gene was located in the BAC18L2. Although Sakabe et al. (1999) reported that MASL1 has a single exon structure, comparison of MASL1 cDNA and BAC18L2 genomic sequences revealed that the exon–intron structure of MASL1 consists of at least three exon structures (Figure 1c and d).

OCI-LY8 has been reported to possess translocations at MYC, BCL2, and BCL6 genes with IgH genes. We confirmed these translocation with FISH analysis (data not shown). BAC/PAC clones used were RP1-80K22 (Accession no. AF315312) for the MYC gene, RP11-299P2 (Accession no. AC022726) for the BCL2 gene, RP11-211G3 (acc no. AC072022) for the BCL6, and RP11-982M15 (Accession no. AL583722) for the IgH gene.

3'RACE analysis

In an attempt to determine whether the MASL1 gene contains a breakpoint, 3' RACE analysis was performed with various primers. It was found that a new sequence different from MASL1 cDNA was introduced at the 3' region of MASL1 cDNA. The new sequence was BLAST searched and found to be 100% identical to the sequence of BAC, BAC326E7 aligned at 14q21. We found that translocated MASL1 produced chimeric transcripts with the '14q21 element' from 3002 bp of MASL1 and was predicted chimeric MASL1 protein. The chimeric transcript has a terminal codon (TGA) at 58 bp from the breakpoint, which yields an additional 19 new amino acids (Figure 3).

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Nucleotide sequences of MASL1 cDNA and chimeric MASL1, and predicted amino-acid sequences near the breakpoint. (a) Part of the MASL1 cDNA sequence is shown. The breakpoint at 8p23.1 in OCI-LY8 is between nucleotides (nt) 3001 and 3002 where exons 1 and 2 are separated. (b) Chimeric MASL1 cDNA and predicted amino-acid sequences near the breakpoint. The sequence of 14q21 element was introduced after nucleotide 3002, resulting in chimeric MASL1 polypeptide with 14q21 element, which yields an additional 19 amino acids. Amino-acid and nucleotide sequences of 14q21 element are shown in light gray boxes. The breakpoint is indicated with the thick arrows. MASL1 exons 1 and 2 are shown at the top with thin arrows. MASL1 and 14q21 element are shown at the bottom with thin arrows. Nucleotides sequences and amino acid that is translocation is underlined. The nucleotides and amino acids at the breakpoint, and the stop codon 'tga' are underlined

Full figure and legend (76K)

RT–PCR

Chimeric and normal mRNAs of MASL1 and the 14q21 element were analysed by RT–PCR. As shown in Figure 4a, MASL1 exon 1 (primer pair 1) was transcribed in seven B-cell lines and fetal brain. Interestingly, when the MASL1 transcript of exons 1–2 (primer pair 2) was used, only OCI-LY8 did not show amplification. This result correlated well with the finding of FISH analysis that the normal allele of MASL1 was deleted (Figure 2a). mRNA of chimeric MASL1 (MASL1-14q21 element) was clearly detected in the OCI-LY8 cell line (primer pair 3). mRNA of chimeric MASL1 and 14q21 element was further examined with 27 cases of diffuse large B-cell lymphoma patients but no chimeric transcript was amplified (data not shown). The transcript of the 14q21 element (primer pair 4) was also examined but no amplification was shown with variety of mRNAs including fetal brain, spleen, liver, lympho-node, skeletal muscle, colon, lung, and heart (data not shown).

Figure 4.
Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

RT–PCR analysis and normal and chimeric MASL1 cDNAs. Lane 1, fetal brain; lane 2, OCI-LY8; lane 3, OCI-LY2; lane 4; OCI-LY3, lane 5; OCI-LY4, lane 6, OCI-LY13.2; lane 7; OCI-LY18. Primer pairs used are depicted schematically below the panel (d and e). (a) RT–PCR analysis using primer pair 1. RT–PCR with primer pair 1 (within the exon 1, nucleotide numbers 2101–2961) shows amplification in every lane. (b) RT–PCR analysis using primer pair 2. RT–PCR using primer pair 2 (exons 1–2, nucleotide numbers 2101–3090) shows amplification in all lanes except for OCI-LY8. (c) RT–PCR analysis using primer pair 3. RT–PCR with primer pair 3 (MASL1 exon 1 to 14q21 element) shows amplification only in OCI-LY8, indicating that chimeric MASL1 gene is transcribed. (d) Schematic illustration of MASL1 cDNA. Exons of the MASL1 gene are shown in the gray box. Plimer pairs 1 and 2 are shown under panel d. Plimer pairs 3 and 4 are shown under panel e. (e) Schmatic illustration of chimeric MASL1 cDNA. 14q21 element are shown in striped box

Full figure and legend (87K)

Focus assay

Focus assays with NIH3T3 were performed to investigate tumorigenic activity of MASL1 and chimeric MASL1 (Table 1). Although ras transfection produced about 300 foci per dish (29.8/10 mug/dish), no obvious foci were detected in transfection with MASL1 or chimeric MASL1.


Nude mice assay (Table 1)

Tumorigenic activity was further investigated with a nude mice assay. Cells (5 times 106) of NIH3T3 cells transfected with MASL1 or chimeric MASL1(MASL1-14q21 element) were inoculated into nude mice, while 3 times 106 NIH3T3 cells transfected with H-ras oncogene were inoculated into nude mice as positive control. The H-ras transfectants produced tumors after day 5, but no signs of tumors were recognized in mice transfected with MASL1 and chimeric MASL1. However, during days 21–28, both mice with MASL1 and with chimeric MASL1 transfectants produced tumors (experiment 1). In the experiment (Exp) 1, transfectants were inoculated 21 days after transfection. Two out of two mice that were injected MASL1 or chimeric MASL1 produced tumors. In order to confirm the tumorigenic activity, transfectants were inoculated 3 days after transfection in Exp 2. Three out of four mice injected with MASL1 transfectants and three out of four mice with chimeric MASL1 transfectants showed tumor growth. Tumorigenic activity was further confirmed in the Exp 3 where transfectants were drug selected for 10 days and were inoculated. In this experiment, four out of six mice with MASL1 transfectants and two out of four mice with chimeric MASL1 transfectants showed tumor growth. None of the mice with the control vector produced any tumors throughout these experiments.

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Discussion

We found that MASL1 is a possible target gene for translocation at 8p23. 1. This translocation was found to result in the chimeric MASL1. The sequence of the 14q21 element did not contain any region homologous with known ESTs or genes, and no expression was detected through RT–PCR analysis with various tissues, which suggests that the 14q21 element may not be an exon of gene. Thus, the 14q21 element is likely to be a 'cryptic' exon. Although we performed RT–PCR analysis for detecting chimeric MASL1 gene against seven B-cell lymphoma cell lines and 27 samples of diffuse large B-cell lymphoma patients, chimeric MASL1 was not detected. Thus, the translocation of MASL1 seems to be an infrequent event in B-cell lymphoma.

Sakabe et al. (1999) pointed out that the MASL1 protein has several domains: ras, three leucine zipper, ATP/GTP-binding site, and leucine-rich tandem repeat motif. The function of normal MASL1, including a possible tumorigenic activity, has not been studied. Focus assays with NIH3T3 were performed to investigate the potential tumorigenic activity of both MASL1 and chimeric MASL1. Although the previous focus assay did not show any transforming activity, our study presented here clearly and for the first time demonstrated its transforming activity in an in vivo tumorigenic assay.

As previously reported, translocations of the BCL2, BCL6, and MYC genes with IgH gene are present in OCI-LY8 (Chang et al., 1995; Chaganti et al., 1998), and it is well established that these translocations play pivotal roles in lymphomagenesis. However, it is conceivable that gene alterations of MASL1 as a result of chromosome translocation may play an additional role in lymphomagenesis because MASL1 was shown to have tumorigenic activity. Further study is needed to explore the mechanism of tumorigenic activity and its transcriptional regulation.

Gene alteration via gene amplification is characteristic of solid tumors and gene alteration via chromosomal translocation is most frequent in and characteristic of hematological malignancies. As seen in our study, a gene amplified in solid tumors can be a target for chromosomal translocation in hematological malignancy. For example, BCL1/cyclinD1 is a target gene for translocation t(11;14)(q13;q32) in mantle cell lymphoma (Seto et al., 1992; Komatsu et al., 1994), while in breast cancer, BCL1/cyclinD1 overexpression occurs in the feature of 'genomic amplifications' instead of translocation (Tanner et al., 1998). The same process is seen in MYC alteration with t(8;14)(q24; q32) in Burkitt lymphoma. MYC is overexpressed in several solid tumors as a result of genomic amplification at the 8q24 region instead of translocation (Gilhuis et al., 2000; Nupponen and Visakorpi, 2000; Stock et al., 2000). MASL1 was identified as a target gene for malignant fibrous histiocytoma, but no evidence of tumorigenic activity has been found. In this study, we found that MASL1 was a target gene in a lymphoma cell line and showed its tumorigenic activity. These results indicate that MASL1 is not only a target gene for genome amplification but also for translocation.

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Materials and methods

OCI-LY8 cell line

The cell line was cultured with RPMI 1640+10% FCS at 37°C. The karyotype is; 46-47,X,der(2)t(2;5)(q35;q31),der(3)t(3;
14)(q27;q32),del(5)(q31q35),del(6)(q22q23)
,t(7;10)(p15;q24),der(8)t(18qtel1 right arrow 8q21double colon14q32 right arrow 14q21double colon8p23.1 right arrow 8q24double colon3q27 right arrow 3qtel),der(8)t(8;17)(p11;q11),der(11)t(11
;17)(q23;q11),der(13)inv(13)(p11q14),del
(13)(q22q31),der(14)t(8;14)(p23.1;q21),
der(14)t(8;14)(q24;q32),del(15)(q15q21),
der(19)t(2;19)(?;p13). The partial karyotype of OCI-LY8 described by Mehra et al. (2002) seems somewhat different from the one we observed in terms of der(8)t(8;14)(p23.1;q32). Our FISH and choromosome painting analyses indicated that it should be changed to der(8)t(18qtel right arrow 18q21double colon14q32 right arrow 14q21double colon8p23.1 right arrow 8q24double colon3q27 right arrow 3qtel).

BAC search

BAC contigs of 8p23.1 were selected from the European Bioinformatics Institute homepage (http://www.ensembl.org/Homo_sa
piens/
). BAC clones were purchased from the BACPAC Resource Center and used for FISH probes.

Genetic information

STSs from the 8p23.1 regions were identified from the NCBI database. Nucleotide homologies were searched with the aid of the Genbank database. The BLAST search was conducted with the NCBI server.

FISH analysis

FISH analysis was performed as described previously (Tagawa et al., 2002). Chromosome 8-specific library DNA was used for dual color FISH (chromosome 8 painting probe, WCP 8 Spectrum Orange; Vysis, Downers Grove, IL, USA). Total DNAs from BAC clones were used as probes for FISH.

3'RACE analysis

3'RACE was performed with the 3'RACE System for rapid amplification of cDNA ends, according to the manufacturer's protocol (Gibco BRL, Gaithersburg, MD, USA) using total RNA of fetal brain and OCI-LY8 cells; 5 mug of the total RNAs were reverse transcribed with an adapter primer (AP). Amplification of the target cDNA was performed with the thermal-cycler PE GeneAmp Systems 2400 (Perkin Elmer) using MASL1 RACE primer 1 (5'-cacgctacagtgtccagatcaaca-3') and universal amplification primer (UAP). The PCR products were diluted 100 times and 1 mul was used as a template of nested amplification. Nested PCRs were performed with MASL1 RACE primer 2 (5'-ctgtccattgctagccatgcatca-3') and with abridged universal amplification primer (AUAP). First and nested PCR were performed by denaturation at 94°C for 45 s, annealing at 60°C for 45 s, and extension at 72°C for 3 min in 30 cycles.

RT–PCR analysis

We used sense and antisense primers and Superscript II (Gibco BRL) to amplify total RNA from cell lines, patient samples, and various human tissues, as well as a commercial preparation of fetal brain total RNA (Clontech, Palo Alto, CA, USA). OCI-LY2, OCI-LY3, OCI-LY4, OCI-LY7, OCI-LY13.2, and OCI-LY18 are the cell lines established at Ontario Center Institute from high-grade malignant lymphomas (Tweeddale et al., 1987). The resultant products were purified and sequenced as described above. Sequences of primers used for the RT–PCR were primer pair 1 (Figure 4a): sense, 5'-cagcgtgccctctcctacctgcatgagagc-3' (MASL1 cDNA nucleotide numbers 2101–2130); antisense, 5'-gcatgtggattgggcgatcctctcttaagg-3' (MASL1 cDNA nucleotide numbers 2990–2961); primer pair 2 (Figure 4b): sense, 5'-cagcgtgccctctcctacctgcatgagagc-3' (MASL1 cDNA nucleotide numbers 2101–2130); antisense, 5'-gcaacccaaggcaacatttactcgctcgct-3' (MASL1 cDNA nucleotide numbers 3090–3061); primer pair 3 (Figure 4c): sense, 5'-cacgctacagtgtccagatcaaca-3' (MASL1 cDNA nucleotide numbers 2687–2717); antisense, 5'-agcagcaaattagagacactttgc-3' (BAC326E7 nucleotide numbers 102 669–102 646); primer pair of 14q21 element (primer pair 4): sense, 5'-cagtgaatctacacgctgagaacc-3' (BAC326E7 nucleotide numbers 102358–102381); antisense, 5'-agcagcaaattagagacactttgc-3' (BAC326E7 nucleotide numbers 102 669–102 646). The thermal-cycler was a PE GeneAmp Systems 2400 (Perkin Elmer, Foster City, CA, USA). Denaturation was performed at 94°C for 1.5 min; annealing and extension steps were performed, respectively, for 1.5 min at 58°C and 2.5 min at 72°C for 30 cycles, respectively. Bands were checked electrophoretically on 1.5% agarose gels in TBE buffer (0.089 M Tris, 2 mM EDTA (pH 8.0)) at 50 V for 60 min.

Nucleotide sequence analysis

Amplified fragments were separated by means of a low-melting point gel electrophoresis and purified, after which 50 ng of fragments was used for direct sequencing with the dideoxy chain termination method using an ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin Elmer).

Constructs of MASL1 and chimeric MASL1

cDNAs containing the open reading frame of MASL1 and chimeric MASL1 were generated with total RNA of fetal brain and OCI-LY8, respectively. The following primers were used for RT–PCR: MASL1 primer sense, 5'-cccaagcttcccgccatggctgggatggacagtggcaa-3'; antisense, 5'-cggaattctcactggtttctgtgcttttcaccaacatt-3'; Chimeric MASL1 primer sense, 5'-cccaagcttcccgccatggctgggatggacagtggcaa-3'; antisense, 5'-cggaattctcagaacaaatgaaaccagtttccactctg-3'. Each fragment was inserted into the cloning site of the pcDNA3.1 (Invitrogen, Carlsbad, CA, USA) vector by means of HindIII and EcoRI digestion.

Focus assay

The constructs of MASL1 (10 mug), chimeric MASL1 (10 mug), and vector (pcDNA3.1, 10 mug) were transfected into NIH3T3 by means of calcium-phosphate precipitation (Sin et al., 1979) with the Profection Mammalian Transfection Systems (Promega, Madison, WI, USA). The culture mediaum was Iscove+10% calf serum, and the positive control activated H-ras (10 mug, plasmid: pEJ6.6). At 2 days after completion of transfection, the cells were trypsinized and split cells were placed in 1/20 in new 100-mm dishes. The Foci were counted on day 21.

Nude mouse assay (Exps 1 and 2)

In the Exp 1, number of foci was counted in focus assay at day 21, and the cells were used for nude mice assay. Cells (5 times 106) were injected subcutaneously at the right and left backs of 7–8-week-old female CD-1 nude mice (Charles River Co., Yokohama, Japan). The tumor growth was monitored twice a week. In Exp 2, 5 times 106 cells of transfectants were injected to the mice 3 days after transfection.

Nude mice assay with drug-selected NIH3T3 cells (Exp 3)

For the nude mouse experiment, drug-elected transfectants were also used (Table 1, experiment 3). In all, 10 mug of construct (MASL1, chimeric MASL1, or vector) was added as a calcium phosphate precipitate to each 100-mm culture dish containing 5 times 105 cells in 10 ml of Iscove+10% calf serum. After incubation for 4 h, dishes were replenished with a fresh medium containing 10% calf serum. After an additional 24 h, the cells in each plate were trypsinized and seeded onto two 100-mm dishes containing 0.4 g of antibiotic G418 (Gibco BRL, Gaithersburg, MD, USA) per liter. Refeeding of the cultures was carried out at 3-day intervals and the plates reached confluency after 10 days. Then, cells were harvested and 3 times 106 cells were injected subcutaneously at the right and left backs of 8-week-old female nude mice.

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Acknowledgements

This work was supported in part by a Grant-in-aid for the Second-Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare Japan; a Grant-in-aid for Science on Primary Areas (Cancer Research); and a Grant-in-aid for Encouragement of Young Scientists from the Ministry of Education, Science and Culture, Japan.

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NEWS AND VIEWS

Algal Toxins

Nature News and Views (02 Dec 1967)