Behavioural Response Alteration in Caenorhabditis elegans to Urine After Surgical Removal of Cancer: Nematode-NOSE (N-NOSE) for Postoperative Evaluation (2024)

Abstract

The technique used for cancer monitoring is essential for effective cancertherapy. Currently, several methods such as diagnostic imaging and biochemicalmarkers have been used for cancer monitoring, but these are invasive and showlow sensitivity. A previous study reported that Caenorhabditiselegans sensitively discriminated patients with cancer from healthysubjects, based on the smell of a urine sample. However, whether C.elegans olfaction can detect the removal of cancerous tumoursremains unknown. This study was conducted to examine C. elegansolfactory behaviour to urine samples collected from 78 patients before and aftersurgery. The diagnostic ability of the technique termed Nematode-NOSE (N-NOSE)was evaluated by receiver operating characteristic (ROC) analysis. The ROC curveof N-NOSE was higher than those of classic tumour markers. Furthermore, weexamined the change in C. elegans olfactory behaviour followingexposure to preoperative and postoperative samples. The results suggest that areduction in attraction indicates the removal of the cancerous tumour. Thisstudy may lead to the development of a noninvasive and highly sensitive tool forevaluating postoperative cancer patients.

Keywords: Caenorhabditis elegans, olfaction, cancer, prognosis, biodiagnosis

Introduction

Cancer is the leading cause of death worldwide, and the number of people with canceris increasing. The major treatments for cancer include surgery, chemotherapy, andradiotherapy.^1-3 Among thesemethods, the prognosis of surgery depends on the complete removal of cancer tissue,as any remaining cancer cells have the potential to spread to other tissues andcause metastasis and recurrence.^4-6 Therefore, postoperativeobservation is important for assessing surgical outcomes.

Several methods have been developed for postoperative evaluation of cancerconditions. Diagnostic imaging methods such as positron emission tomography–computedtomography and endoscopy have been used for follow-up examination aftersurgery;^7,8however, these methods can be invasive or costly, and their repeated application is limited.⁹ Classic biochemical markers, such as carcinoembryonic antigen (CEA) andcarbohydrate antigen 19-9 (CA19-9), have been used for postoperative monitoring ofpatients with cancer.^10,11 Although these methods are relatively noninvasive, theirsensitivity must be improved.^12,13 Therefore, noninvasive,low-cost, and highly sensitive methods are needed for monitoring patients withcancer after surgery.

A recent study reported that the olfactory behaviour of the nematodeCaenorhabditis elegans to human urine can be utilized todiscriminate patients with cancer from healthy people.¹⁴C. elegans showed an innate attractive behaviour towards urine frompatients with cancer, whereas they avoided urine from healthy subjects. Attractiveolfactory sensory neurons of C. elegans consistently responded tourine from patients with cancer, and aversive sensory neurons have a role inresponse to urine from healthy subjects.¹⁴ Based on the olfactory response of C. elegans, a novelcancer screening test was developed, named Nematode-NOSE (N-NOSE), which wasreferred to as the nematode scent detection test (NSDT) in a previous study.¹⁴ Both the sensitivity and specificity of N-NOSE, including those forearly-stage cancers, were more than 90%. Nematode-NOSE can detect broad types ofcancers including most gastrointestinal cancers.¹⁴

However, whether N-NOSE can be used to monitor the progress of cancer in the samepatient remains unclear. The previous study indicated that C.elegans detected cancer-specific odours in urine from cancer patients,even when the cancer was in stage 0 or I,¹⁴ suggesting that C. elegans sensitively detect the potentialfor cancer development. As postoperative patients have a history of carcinogenesisand potential for recurrence, C. elegans may fail to show aversivebehaviour to the urine samples clearly. We therefore hypothesized that the degree ofattractive behaviour to postoperative urine is decreased compared to preoperativeurine.

In this study, we investigated the ability of N-NOSE as a postoperative tool formonitoring the removal of cancer. We first performed receiver operatingcharacteristic (ROC) analysis to compare the diagnostic performance of N-NOSE andconventional tumour markers, CEA and CA19-9. We next tested our hypothesis andexamined alterations in C. elegans olfactory behaviour betweenpreoperative and postoperative samples from the same patient. Our resultsdemonstrated that the reduction in attractive olfactory behaviour for postoperativesamples indicates the removal of cancer. This study may lead to the development ofan effective tool for postoperative evaluation based on C. elegansolfaction.

Results

To examine the diagnostic performance of N-NOSE for monitoring the removal of cancer,we performed ROC analysis using preoperative and postoperative samples from the samepatient (N = 78 patients; Table1). Conventionally, ROC analysis has been used to quantify how accuratelya medical diagnostic tool can discriminate between 2 groups (eg, cancer patients andhealthy subjects). In this study, ROC analysis was used to quantify thedifferentiation between preoperative and postoperative samples to investigatewhether chemotaxis index (see Methods) reflects the removal of cancer. Valuesobtained for N-NOSE, CEA, and CA19-9 are listed in Supplementary Table S1. Chemotaxis indices of each patient werelisted in Supplementary Table S2. The area under the curve (AUC) indicates theusefulness of N-NOSE, AUC = 0.742, P < .001, 95% confidenceinterval (CI): 0.664-0.819, compared to that of classic tumour markers, CEA(AUC = 0.638, P = .003, 95% CI: 0.551-0.724) and CA19-9(AUC = 0.570, P = .133, 95% CI: 0.480-0.660), for diagnosing theremoval of cancer (Figure 1,Table 2).Furthermore, we examined the diagnostic ability of N-NOSE for different pathologicalstages and cancer types. In stages 0 and I cancer, the AUC of N-NOSE was higher thanthose of CEA and CA19-9 (Figure2, Table 3).In addition, in the 2 types of cancer, the AUC of N-NOSE was higher than those ofCEA and CA19-9 (Figure 3,Table 4). Imagesshowing animals were attracted to the preoperative sample, but not to thepostoperative are described in Supplementary Figure S1. These results suggest that N-NOSE detectedthe removal of cancer more sensitively than the classical tumour markers.

Table 1.

Patient characteristics.

Characteristics	Colorectal cancer patients (N = 46)	Gastric cancer patients (N = 32)	Total (N = 78)
Age (years)
Mean ± SD	67.4 ± 12.1	67.0 ± 10.8	67.3 ± 11.5
Range	35-86	43-89	35-89
Gender
Female	19	8	27
Male	27	24	51
Tumour stage
0-I	15	24	39
II	15	6	21
III-IV	16	2	18

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Abbreviations: SD: standard deviation.

Behavioural Response Alteration in Caenorhabditis elegans to Urine After Surgical Removal of Cancer: Nematode-NOSE (N-NOSE) for Postoperative Evaluation (1)

Table 2.

ROC analysis results.

	AUC	P-value	95% confidence interval
N-NOSE	0.742	<.001	0.664-0.819
CEA	0.638	.003	0.551-0.724
CA19-9	0.570	.133	0.480-0.660

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Figure 2.

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Table 3.

Results of ROC analysis by pathological stage.

	AUC	P-value	95% confidence interval
N-NOSE
Stages 0 and I	0.771	<.001	0.669-0.874
Stage II	0.703	.024	0.544-0.862
Stages III and IV	0.731	.018	0.560-0.903
CEA
Stages 0 and I	0.560	.358	0.432-0.689
Stage II	0.681	.044	0.521-.842
Stages III and IV	0.769	.006	0.605-0.932
CA19-9
Stages 0 and I	0.537	.576	0.408-0.666
Stage II	0.552	.563	0.355-0.729
Stages III and IV	0.667	.088	0.487-0.846

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Abbreviations: AUC, area under the curve; CA19-9, carbohydrate antigen19-9; CEA, carcinoembryonic antigen; N-NOSE, Nematode-NOSE; ROC,receiver operating characteristic.

The results correspond to those shown in Figure 2. TheP-values indicate whether the value of AUC issignificantly different from the value of .5 AUC. The n is the number ofthe chemotaxis indices or values of tumour markers.

Figure 3.

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Table 4.

Results of ROC analysis by cancer type.

	AUC	P-value	95% confidence interval
Colorectal cancer
N-NOSE	0.716	<.001	0.611-0.821
CEA	0.688	.002	0.579-0.796
CA19-9	0.597	.109	0.481-0.714
Gastric cancer
N-NOSE	0.765	<.001	0.647-0.882
CEA	0.554	.456	0.413-0.696
CA19-9	0.521	.778	0.378-0.664

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Abbreviations: AUC, area under the curve; CA19-9, carbohydrate antigen19-9; CEA, carcinoembryonic antigen; N-NOSE, Nematode-NOSE; ROC,receiver operating characteristic.

The results correspond to those shown in Figure 3. TheP-values indicate whether the value of AUC issignificantly different from the value of 0.5 AUC. The n is the numberof the chemotaxis indices or values of tumour markers.

We next investigated whether N-NOSE can indicate the removal of cancer. To evaluatewhether the removal of cancer induced a reduction in attractive behaviour, weanalysed changes in the chemotaxis index using preoperative to postoperative samplesfrom the same patient. Among the 78 samples, 59 samples showed a reduced chemotaxisindex from preoperative to postoperative samples (Figure 4). One-sample t-testrevealed that the differences of the preoperative and postoperative chemotaxis indexwere significantly different from 0 (mean ± standard error of theM: −0.066 ± 0.013, t = −5.053,P < .0001). These results suggest that decreased attractiveolfactory behaviour of C. elegans can indicate the removal ofcancerous tumours.

Discussion

We investigated the use of N-NOSE as a postoperative tool for monitoring the presenceof cancer. We found that N-NOSE showed a higher area under the ROC curves than CEAand CA19-9. In the comparison of the area under ROC curve by pathological stage andcancer type, N-NOSE showed a higher area under the ROC than CEA and CA19-9. We thenfocused on changes in the chemotaxis index in individual samples. Among the 78samples, 59 samples showed a decreased chemotaxis index in postoperative samples,supporting our hypothesis. These results indicate that N-NOSE is a useful surrogatemarker for detecting the postoperative cancer status.

We investigated the diagnostic ability of N-NOSE to detect the removal of canceroustumours. The ROC analysis revealed that N-NOSE was more accurate than CEA or CA19-9(Figure 1). Thedetection ability of C. elegans olfaction was validated in 2 typesof cancer (ie, colorectal and gastric cancer) and pathological stages (Figures 2 and 3, Tables 3 and 4). The results revealed that C.elegans can detect cancer regardless of the types and stages.¹⁴ In stages 0 and I cancers, CEA and CA19-9 showed nearly negative results, inwhich the classic tumour markers showed less than 0.6 AUC values (Figure 2A and Table 3) and then we couldnot use these markers as indicators of cancer removal. In contrast, N-NOSE coulddiscriminate the preoperative and postoperative status even in stages 0 and Icancers. These results suggest that N-NOSE can detect cancer removal regardless ofthe number of cancer cells present. In gastric cancers, compared to colorectalcancers, N-NOSE showed a higher AUC than the classical tumour markers. This may bebecause more early-stage patients were included in the gastric cancer group (ie, 24of 32 samples were from stages 0 and I cancer patients). Analysis of the changes inC. elegans olfaction also revealed the ability to detect cancerremoval in the same individuals (Figure 4). Furthermore, the follow-up test using 3 samples showingrecurrence supported the clinical usefulness of N-NOSE. In these 3 samples, thechemotaxis index was decreased following cancer removal and increased followingrecurrence (patient A; preoperative index = 0.027, postoperative index = −0.016, andrecurrence index = 0.002, patient B; preoperative index = 0.095, postoperativeindex = −0.148, and recurrence index = 0.034, patient C; preoperative index = 0.027,postoperative index = 0.023, and recurrence index = 0.067, Supplementary Figure S2). For example, patient B was a female withstage II rectal cancer. Her CEA and CA19-9 levels were sustained within the normallimit during follow-up regardless of surgery or recurrence. In contrast, thechemotaxis index changed as described above, reflecting removal and recurrence. Wealso found that in several stage IV patients who underwent palliative surgery, thechemotaxis index changed according to their tumour volumes (Supplementary Figure S3), in which the tumour volume was measuredaccording to revised RECIST guideline (version 1.1).¹⁵ The chemotaxis index decreased when the primary sites were removed and thenincreased when metastatic sites increased. These results suggest that N-NOSE has thepotential to be a postoperative tool for monitoring cancer.

Our results suggest that the olfactory behaviour of C. elegansreflected the change in urinary cancer-specific odour caused by surgical removal.Previous studies showed that urinary chemical components, including volatilecomponents, in patients with cancer different from those in controlsubjects,^16-18 and thepattern of urinary components were changed by surgical therapy.¹⁹ Such changes were detected by C. elegans in this study.C. elegans showed dose-dependent olfactory behaviour, withattractive behaviour to attractants corresponding to the concentration of spottedodour samples.^20-24 These results support those ofthe current study.

Our results showed that N-NOSE had a higher AUC than CEA and CA19-9 except for in thediagnosis of stages III and IV disease (Figure 2C, Table 3), although the classic tumourmarkers also showed decreased values in postoperative samples (Supplementary Table S1). The superiority of N-NOSE in the AUC may beexplained by the distribution of values. The values for CEA and CA19-9 are individual-specific,²⁵ and such dispersion may lead to relatively low diagnostic performance.Indeed, the ranges of values for CEA and CA19-9 in this study were 0.5 to 476.9 and0.1 to 82 171.4, respectively. The values of CEA and CA19-9 indicate theirconcentrations in serum, and individual difference is directly reflected by thevalues. In contrast, in N-NOSE, the chemotaxis index is a normalized value thatindicates the ratio of animals showing attractive behaviour to the spotted sample.Thus, the value showed a relatively low distribution compared to the classic tumourmarkers. Such characteristics may also contribute to diagnostic performance in ourresults. However, the normalization in chemotaxis index might account for thedifference of AUC in our results, which might be noted as limitation. To compare thediagnostic abilities more impartially, other response of C. elegansto urine, such as olfactory neural response, could be utilized instead ofbehavioural response.

There were some limitations to this study. Our results suggest that the absolutevalue of the chemotaxis index might be unsuitable for indicating cancer removal. Theanimals did not show aversive behaviour to postoperative urine, with only 32 urinesamples showing a negative chemotaxis index in postoperative samples compared to 63samples showing a positive chemotaxis index preoperatively. This may be becausepostoperative patients have some differences from healthy subjects, such as ahistory of carcinogenesis and the potential for recurrence. In addition, patientswith cancer utilize unique metabolic pathways that have residual effects onpostoperative urine samples. Indeed, several reports showed that urine from patientswith cancer have a specific pattern of bioactive molecules, such as DNA, miRNA, andextracellular vesicle proteins.^1,26,27 Thus, C.elegans would fail to show aversive behaviour in postoperative samples.Furthermore, several postoperative samples showed an increased chemotaxis index(Figure 4). Studies areneeded to identify the factors that increase the chemotaxis index in postoperativesamples. The premise of ROC analysis might not be congruent with this study. The ROCcurve relies on a measure of ‘true positives’ and ‘true negative’. Although weconfirmed that the tumour was removed from the patient by intraoperative macroscopicfindings, histopathological examination, and postoperative imaging inspection, therecurrence was found (Supplementary Figure S2). An alternative analysis, which iscongruent with this study and enables to examine the resolution from preoperative topostoperative samples, might be needed. There may be a limitation that the method ofN-NOSE can be optimized to make larger different chemotaxis indices betweenpreoperative and postoperative samples. For example, in Supplementary Figure S2, patients A and C showed no significance,though the alteration of chemotaxis index could trace the condition of cancer (ie,decreased by removal of cancer and increased by recurrence). For the optimization ofN-NOSE with more accuracy, other chemotaxis assay formats and devices could beutilized. In past C. elegans studies, several methods were used toinvestigate and examine the olfactory behaviour of C. elegans indetail, such as single animal assay,²⁴ animal tracking system,²⁴ and monitoring neural response in moving animals.²¹ Otherwise, identification of cancer-specific odourants and the olfactoryreceptor could also lead to optimization of N-NOSE. Based on the previous studiessuggesting the cancer-specific odourants,^16-18 method of N-NOSE assay couldbe enhanced more accurately. Furthermore, no individual-specific normalization ofurine samples was performed due to following the previous study.¹⁴ The normalization of urine concentration might lead to the optimization.Those methods of optimization would help to brush up N-NOSE as a more accuratetechnique to monitor preoperative patients. The analysis of other types of cancermight be needed. In this study, only 2 types of cancer (ie, colorectal and gastriccancer) were tested. Although the previous study showed that N-NOSE can detectseveral types of cancer,¹⁴ more number of types of cancer should be analysed to investigate thecapability of N-NOSE for prognosis.

In conclusion, we demonstrated that N-NOSE can reflect the removal of canceroustumours using preoperative and postoperative urine samples collected from patients.Nematode-NOSE shows potential as a tool for monitoring cancer in patients as well asfor detecting cancer.

Methods

Study populations

Urine samples were collected from 78 patients (age of mean ± SD = 67.3 ± 11.5,female:male = 27:51) who were diagnosed as cancer at the Nanpuh Hospital(Kagoshima, Japan) between June 2016 and February 2018. The characteristics ofthe patients are listed in Table 1. Measurement was performed within 60 days before and aftersurgery. Multiple cancers were excluded. Preoperative urine was collected before26 ± 11 (mean ± SD) days, while postoperative urine was collected after 29 ± 9(mean ± SD) days. In all patients, the pathologic stages were determined byhistological diagnosis of the primary tumour. The classical tumour markers CEAand CA19-9 were also measured in the patients. Blood samples were collectedbefore 26 ± 11 and after 28 ± 9 days of surgery. Collected urine samples werestored frozen until analysis by N-NOSE. The volume of tumour was measuredaccording to revised RECIST guideline (version 1.1).¹⁵ Briefly, the targeted tumour was picked out up to 10 pieces, then the sumof the maximum lengths of the tumour pieces was calculated in the preoperative,postoperative, and recurred samples.

The study was approved by the Ethics Committee of Nanpuh Hospital, KagoshimaKyosaikai, Public Interest, Inc. Association, Japan. Clinical examinations wereperformed according to the principles of the Declaration of Helsinki. Researchconsent was obtained in writing from each patient. Informed consent was obtainedfrom all participants. The first author guarantees the accuracy and completenessof the data and analysis and of the study’s fidelity regarding technical andbiostatistics protocols.

Measurement by N-NOSE

Nematode-NOSE detects cancer by sensing a distinguishable cancer odour in urineusing the C. elegans olfactory system.¹⁴ The olfactory behaviour of C. elegans was evaluated bypopulation assays, which was in accordance with the classical method by Bargmannet al.²⁰ This method uses the chemotactic attraction or avoidance of C.elegans to odourants in urine. C. elegans(wild-type N2) were cultured at 20°C under well-fed and uncrowded conditionswith the Escherichia coli strain NA22 as a food source.Chemotaxis assays with human urine were performed on 9-cm plates containing10-mL 2% agar, 5 mM KPO₄, 1 mM CaCl₂, and 1 mMMgSO₄ as previously described.^14,20,24 Chemotaxis assays wereconducted as described previously.¹⁴ Briefly, 1 μL of urine was added at 2 spots on one end of the assayplates, and 0.5 μL of 1 M sodium azide was added at 2 spots on both ends of theplates. As the diluent of urine samples, we used water, and we confirmed thatanimals showed no chemotaxis behaviour to 1 µL of water. Thus, no diluent wasput on the opposite side of the plate. Animals were collected, washed 3 timeswith chemotaxis buffer (0.05% gelatine, 5 mM KPO₄, 1 mMCaCl₂, and 1 mM MgSO₄), and transferred to the centreof the plate to move freely for 30 min. Approximately 50 to 100 synchronizedyoung adults were used per plate. The chemotaxis index was calculated as thenumber of animals in the region near the urine samples minus the animals in theregion without the samples divided by the total number of animals.^14,24 The formatof an agar plate to count animals is described in Supplementary Figure S4. The average chemotaxis indices of morethan 10 assay plates were determined. Hirotsu et al¹⁴ reported that the chemotaxis index is positive in urine samples frompatients with diluted by 10- to 1000-fold and is not observed in urine samplesfrom healthy volunteers. Therefore, running behaviour against 10- to 1000-folddiluted urine was investigated; positive peaks were considered as positiveresults, and a lack of chemotaxis was considered as a negative result. In thisstudy, the result of N-NOSE was obtained using 10-fold diluted urine samples. Weperformed 2 sets of chemotaxis assay, in which the one was for preoperativeurine samples, and the other was for postoperative samples.

Statistical analyses

Receiver operating characteristic analysis was performed based on logisticregression using SPSS, version 25 (IBM Co, Armonk, NY, USA). A value ofP < .05 was considered significant. In ROC analysis,chemotaxis indices listed in Supplementary Table S2 were used, in which the preoperativechemotaxis indices were considered as cancer samples, and postoperative indiceswere considered as healthy samples. In ROC analysis, the asymptotic significance(null hypothesis: AUC = 0.5, α level = 0.05) was obtained, which indicates thereliability of the AUC (ie, whether the value of AUC is significantly differentfrom the value of 0.5 AUC).

Supplemental Material

Revised_SupplementaryInformation_4_xyz2778816687648 – Supplementalmaterial for Behavioural Response Alteration in Caenorhabditiselegans to Urine After Surgical Removal of Cancer:Nematode-NOSE (N-NOSE) for Postoperative Evaluation

Click here for additional data file.^{(405.1KB, pdf)}

Supplemental material, Revised_SupplementaryInformation_4_xyz2778816687648 forBehavioural Response Alteration in Caenorhabditis elegans toUrine After Surgical Removal of Cancer: Nematode-NOSE (N-NOSE) for PostoperativeEvaluation by Hirotake Kusumoto, Kotaro Tashiro, Syunji Shimaoka, KoichiroTsukasa, Yukiko Baba, Saori Furukawa, Junichiro Furukawa, Toyokuni Suenaga,Masaki Kitazono, Sadao Tanaka, Toru Niihara, Takaaki Hirotsu and Takayuki Uozumiin Biomarkers in Cancer

Acknowledgments

The authors appreciate the support of the Division of Clinical Laboratory andClinical Application of Nanpuh Hospital.

Footnotes

Funding:The author(s) received no financial support for the research, authorship, and/orpublication of this article.

Declaration of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to theresearch, authorship, and/or publication of this article.

When the study was started, the author belonged to the affiliation of “4” and“5”, and in the end of the experiments, the author belonged to the affiliationof “4” and “6”

Author Contributions: H.K., T.H., and T.U. designed the conception of the study. T.H. and T.U. made theexperimental design of the N-NOSE test. T.N., J.F., S.F., Y.B., K.T., S.S.,K.T., and M.K. collected urine and serum samples from the participants. T.N.,T.S., and S.T. evaluated clinical data. H.K., T.Y., T.U., and T.H. interpretedthe results. H.K., T.U., and T.H. made and modified the manuscript.

Data Availability: The data that support the findings of this study are available from thecorresponding author, upon reasonable request.

ORCID iD: Takayuki Uozumi https://orcid.org/0000-0002-6107-3452

Supplemental Material: Supplemental material for this article is available online.

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Associated Data

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Supplementary Materials

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Behavioural Response Alteration in Caenorhabditis elegans to Urine After Surgical Removal of Cancer: Nematode-NOSE (N-NOSE) for Postoperative Evaluation (2024)

Abstract

Introduction

Results

Table 1.

Figure 1.

Table 2.

Figure 2.

Table 3.

Figure 3.

Table 4.

Figure 4.

Discussion

Methods

Study populations

Measurement by N-NOSE

Statistical analyses

Supplemental Material

Acknowledgments

Footnotes

References

Associated Data

Supplementary Materials