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. 2015 Mar 11;10(3):e0118699.
doi: 10.1371/journal.pone.0118699. eCollection 2015.

A highly accurate inclusive cancer screening test using Caenorhabditis elegans scent detection

Takaaki Hirotsu  1 , Hideto Sonoda  2 , Takayuki Uozumi  3 , Yoshiaki Shinden  4 , Koshi Mimori  4 , Yoshihiko Maehara  5 , Naoko Ueda  6 , Masayuki Hamakawa  3
Affiliations

A highly accurate inclusive cancer screening test using Caenorhabditis elegans scent detection

Takaaki Hirotsu et al. PLoS One. .

Abstract

Early detection and treatment are of vital importance to the successful eradication of various cancers, and development of economical and non-invasive novel cancer screening systems is critical. Previous reports using canine scent detection demonstrated the existence of cancer-specific odours. However, it is difficult to introduce canine scent recognition into clinical practice because of the need to maintain accuracy. In this study, we developed a Nematode Scent Detection Test (NSDT) using Caenorhabditis elegans to provide a novel highly accurate cancer detection system that is economical, painless, rapid and convenient. We demonstrated wild-type C. elegans displayed attractive chemotaxis towards human cancer cell secretions, cancer tissues and urine from cancer patients but avoided control urine; in parallel, the response of the olfactory neurons of C. elegans to the urine from cancer patients was significantly stronger than to control urine. In contrast, G protein α mutants and olfactory neurons-ablated animals were not attracted to cancer patient urine, suggesting that C. elegans senses odours in urine. We tested 242 samples to measure the performance of the NSDT, and found the sensitivity was 95.8%; this is markedly higher than that of other existing tumour markers. Furthermore, the specificity was 95.0%. Importantly, this test was able to diagnose various cancer types tested at the early stage (stage 0 or 1). To conclude, C. elegans scent-based analyses might provide a new strategy to detect and study disease-associated scents.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. C. elegans can respond to cancer cell culture medium and cancer tissue, and detect cancer smells in human urine.
(A) Chemotaxis of wild-type C. elegans to 10-6 and 10-7 dilutions of MEM, EMEM or RPMI medium only, or culture medium from fibroblast (KMST-6 and CCD-112CoN), colorectal cancer (SW480, COLO201 and COLO205), breast cancer (MCF7) or gastric cancer (NUGC4, MKN1 and MKN7) cells (n ≥ 5 assays). (B) Chemotaxis of wild type and odr-3 mutants (n ≥ 5 assays) in response to a 10-6 dilution of conditioned culture medium from colorectal, breast or gastric cancer cells. (C) Chemotaxis of wild type to 10-2, 10-3 and 10-4 dilutions of saline with normal and cancer tissue (n ≥ 5 assays). (D) Chemotaxis to normal and cancer tissue by wild-type and odr-3 mutants (n ≥ 5 assays). (E) Chemotaxis of wild type to human urine samples from control subjects (blue bars; c1–c10) or cancer patients (orange bars; p1–p20) at 10-1 dilution (n = 5 assays). (F) Chemotaxis to urine from cancer patients by wild-type and odr-3 mutants at 10-1 dilution (n ≥ 6 assays). Error bars represent SEM. Significant differences from control samples are indicated by * (P < 0.05); ** (P < 0.01); *** (P < 0.001) by Dunnett’s tests (A) or Student’s t-tests (B, C, D, F). † indicates a significant difference (P < 0.05) by Student’s t-tests (A).
Fig 2
Fig 2. Olfactory neurons of C. elegans respond to urine from cancer patients.
(A) Chemotaxis to urine from controls (c5 and c10) or cancer patients (p5, p8 and p18) in wild-type animals with AWC, AWA, ASH or AWB neuron ablation (n ≥ 5 assays). (B) Chemotaxis of wild-type C. elegans to urine samples from controls (A and B) or cancer patients (C and D) with or without filtration that were used in imaging experiments (n ≥ 5 assays). Filtration of urine had no significant effect. (C) Calcium responses of AWC olfactory neurons on removal of control or cancer patient urine. (D) Average fluorescence changes in AWC for 10 s following urine removal (n ≥ 8 animals). Values are normalized to the average change in ratio of Control-A. (E) Calcium responses of AWA olfactory neurons after addition of urine from controls or cancer patients. (F) Average fluorescence changes in AWA for 10 s after urine stimulation (n ≥ 8 animals). Values are normalized to the average change in ratio of Control-A. The brown shading indicates that urine was present. Error bars and shaded regions around the curves represent SEM. Significant differences from control samples are indicated by * (P < 0.05); ** (P < 0.01); *** (P < 0.001) as calculated by Dunnett’s tests (A, D, F).
Fig 3
Fig 3. NSDT of 242 urine samples.
Box plots (A) and dot plots (B) of chemotactic responses of wild-type C. elegans to urine samples from control subjects (n = 218) or cancer patients (n = 24). Whiskers indicate 10th and 90th percentiles.
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Publication types

Grants and funding

This research was supported by a JSPS Grant-in-aid for Young Scientists (A), Grant-in-Aid for Scientific Research (C), Senri Life Science Foundation, Inamori Foundation, The Kurata Memorial Hitachi Science and Technology Foundation, The Japan Health Foundation, Mishima Kaiun Memorial Foundation and Kyushu University Interdisciplinary Programs in Education and Projects in Research Development (Type E-4, 24425). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.