Page 68 - JCTR-11-3

Journal of Clinical and
Translational Research N-NOSE: Early cervical cancer screening

1. Introduction animal olfactory systems. While trained detection dogs
have shown promise, their practicality is limited by the
According to the World Health Organization (WHO), extensive training requirements. 13-16 An alternative is
around 660,000 new cases of cervical cancer were diagnosed Caenorhabditis elegans, a well-studied nematode with
globally in 2022; with 94% of the 350,000 related deaths a fully sequenced genome. Its robust olfactory system,
occurring in low- and middle-income countries. This comprising about 1,200 olfactory receptor-like genes, 17,18
1
statistic highlights the critical need for ongoing efforts in enables sophisticated chemotactic behavior. Hirotsu et al.,
19
prevention, screening, and treatment strategies to improve discovered that wild-type C. elegans are more attracted to
women’s health.
cancer cell secretions, tissues, and urine from colorectal,
The etiology of cervical cancer is closely linked to gastric, and breast cancer patients while avoiding healthy
human papillomavirus (HPV) infection, with high-risk urine samples. This response is possibly due to olfactory
strains HPV-16 and HPV-18 responsible for most high- sensory neurons detecting cancer-associated volatile
grade cervical pre-cancers. These strains play a pivotal organic compounds (VOCs). 20,21
2,3
role in the disease’s pathogenesis by integrating their DNA
into host cells and disrupting normal cell cycle regulation. Building on this concept, our research team developed
As illustrated in Figure 1, cervical carcinogenesis typically an innovative cancer screening tool called “Nematode-
begins with the development of cervical intraepithelial NOSE” (N-NOSE). This method has successfully detected
neoplasia (CIN), progressing from mild dysplasia over 20 types of malignancies, including the most common
(e.g., CIN1) to more severe stages, such as CIN3, which types of cancer worldwide, such as lung, stomach,
is considered a pre-cursor to invasive cervical cancer. colorectal, breast, cervical, and prostate cancers, as well as
This study focuses particularly on the detection of CIN various digestive cancers – including esophagus, bile duct,
and CIN3, as these stages represent critical windows for gallbladder, and pancreas cancers. 19,22-24 The present study
intervention before the disease progresses to invasive evaluates the efficacy of N-NOSE in detecting progressive
cancer. 4,5 cervical carcinogenesis. Using urine samples from
74 female patients with cervical cancer and 245 female
While most cases of mild dysplasia, such as CIN1 or patients with CIN, we investigate the potential of N-NOSE
low-grade squamous intraepithelial lesions, may resolve to detect CIN as a pre-cancer stage with high sensitivity,
due to the host’s immune response, CIN2 and CIN3 as well as its ability to identify cervical cancer. This
(known as high-grade squamous intraepithelial lesions) research contributes to the growing evidence supporting
infected with high-risk HPV types are considered true pre- nematode-based cancer screening methods and explores
cursor states for cervical cancer. their potential application in cervical cancer detection and
6-8
Although HPV vaccination and traditional screening prevention. Our research also aims to establish N-NOSE
methods, such as cytology and histology, have contributed as a reliable, non-invasive diagnostic tool with heightened
to prevention efforts, a significant disparity in the global sensitivity, which could revolutionize screening and early
burden of cervical cancer remains. Early detection of detection in cervical health.
9
CIN, representing the transformational phase of cervical
cells, is pivotal in preventing CIN progression to invasive 2. Materials and methods
cervical malignancy, thereby improving patient prognosis 2.1. Study design and participants
and survival rates. 10,11 As a pre-cancerous condition, CIN
offers a critical window for intervention that can halt the This study was approved by the Ethics Committee of the
disease advancement. 12 National Hospital Organization Shikoku Cancer Center
Hospital, Ehime, Japan. The study design involved the
The early detection of cervical carcinogenesis is prospective collection of urine samples from a cohort of
hindered by several factors, including inadequate screening female patients diagnosed with cervical cancer (n = 74,
coverage due to geographical, economic, and cultural mean age: 51.9 ± 13.4 years) or CIN (n = 245, mean age:
barriers, as well as the accuracy limitations of screening 39.5 ± 11.8 years) at the hospital between May 2017 and
methods, which may result in false negatives or positives. March 2021. Patients in the cervical cancer cohort were
Additional challenges include ensuring patient compliance histopathologically confirmed to have invasive disease.
with follow-up care, determining optimal timing and In contrast, those in the CIN cohort were found to have
frequency of screenings, and the availability of advanced pre-invasive lesions, identified through standard cervical
screening technologies in resource-limited settings. cytology and subsequent detailed examinations, and
Recent advancements in biological diagnostics classified according to the Bethesda System 2001 as CIN1,
have focused on cancer detection, including the use of CIN2, or CIN3. For the purpose of statistical analysis,
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Volume 11 Issue 3 (2025) 62 doi: 10.36922/jctr.24.00080