Metabolomic profiling for early cancer detection: current status and future prospects

KEYWORDS:

• Metabolomics
• cancer
• biomarker
• profiling

1. Introduction

Cancer is a leading cause of mortality in the United States with the number of new cases expected to rise to 22 million individuals within the next two decades. National expenditures for cancer care and treatment were nearly $125 billion in 2010 and are projected to reach $156 billion by 2020 [1]. The case for early cancer detection has never been stronger as it has become increasingly clear that early detection of cancers results in more efficient and targeted treatments, and ultimately leads to lower mortality rates. Finding sensitive and specific biomarkers for early malignancy has been a decade-long endeavor with minimal success, likely due to the simple fact that cancer is not one disease and even a single-site cancer is quite heterogeneous [2,3]. While the technique of metabolomics has been a relative newcomer to the biomarker field, it has, at least initially, been somewhat disappointing in the biomarker arena; however, given the many groups involved with both metabolomics and biomarker discovery, there is considerable optimism in the field that this work will ultimately yield clinically useful cancer biomarkers. Here we will discuss the current status and future prospects of utilizing metabolomics profiling for early cancer diagnoses.

2. Metabolomic profiling: benefits

Metabolomics is an analytical technique that examines all (in theory) small molecule metabolites less than approximately 1 kDa in a biofluid (plasma or urine) or tissue. Practically, it is more common to identify ~300 or so metabolites which have higher abundance and a few hundred more which are not readily identifiable (the ‘unknowns’). Once analyzed with the appropriate statistical methods, a typical metabolomics experiment can yield a metabolite ‘signature’ that differentiates cancer versus a normal state [4]. Unlike transcriptomics and proteomics where modification of substrates commonly occurs, metabolomics can additionally provide insight into disease mechanism as it can identify metabolites that are directly produced in response to cancer or toxicity [4] and can lead to druggable pathways which are altered in the disease process [5]; this aspect of metabolomics, though perhaps more promising than biomarker development, will not be discussed in this Editorial.

Cancer is particularly well-suited for metabolomic profiling since most tumor cells are highly metabolically active and hence evolve profound changes in a number of metabolic pathways (for example glycolysis, amino acid metabolism, fatty acid oxidation) in order to meet their high energy requirements to continue rapid cell growth [6]. Therefore, cancer cells can, in theory, be differentiated from healthy cells by analyzing their metabolic profile [4], which is in fact the very ‘signature’ of altered metabolism.

3. Promising metabolic profiling studies for early cancer detection

The discovery of metabolites in biofluids for early cancer diagnosis has been a disappointing adventure because, as yet, there are few readily available and clinically useful metabolite-based early cancer diagnostic tests to come out of this field, a circumstance which is clearly not due to lack of research in the area. As mentioned, this is likely due to the heterogeneity of cancer as well as the very high bar which is required for a biomarker to screen millions of asymptomatic individuals.

There exist several metabolomic profiling studies that have aimed to identify novel biomarkers for use in cancer diagnostics, yet many of them have not been validated in the original studies or subsequently and thus offer little clinical value. However, there are some notable metabolites that have been clinically validated and are currently being used for diagnostics. Total choline levels are consistently elevated in breast cancer when compared to normal tissue and assessment of choline levels in breast cancer by magnetic resonance imaging spectroscopic imaging (MRSI) can differentiate between normal and cancerous tissue with a sensitivity of 100% [7]. Men with prostate cancer exhibit decreased levels of citrate in prostatic fluid when compared to noncancer patients. Detection of citrate in prostatic fluid by ¹H-NMR, a common metabolite detection technology, was more reliable than using prostate-specific antigen for cancer detection [8]. Furthermore, MRSI citrate detection provides better detection and localization of prostate cancer than use of magnetic resonance imaging (MRI) alone [9]. Additionally, Metabolomic Technologies Inc. recently released the first urine metabolomics screening test for colon cancer, Polyp DX, by utilizing a defined diagnostic metabolomic profile for identifying colonic adenomas with a sensitivity and specificity of 82.7% and 51.2%, respectively [10,11].

There are several metabolomics-based analytical techniques that can be used in vivo and could be considered an extension of metabolomics techniques to the clinic. MRSI is an MRI-related technology that provides noninvasive in vivo spatial distribution of specific metabolites without exposing patients to ionizing radiation. Positron emission tomography is another in vivo metabolic imaging technology that uses radioactively labeled metabolites, such as glucose and glutamine, to evaluate metabolite levels and distribution. These studies demonstrate the efficacy and potential utility of using metabolomics for cancer diagnosis, especially as some tests are now covered by insurance providers [reviewed in 12].

4. Metabolomic profiling: limitations

Despite significant advances in identifying altered metabolites and metabolic pathways in cancer, there are several limitations that have challenged the clinical development of metabolomic profiling for early cancer diagnosis. First, many altered metabolites and metabolic pathways found to be significantly different in vitro or in animal models are found to be biologically insignificant in human studies or do not have sufficiently adequate performance to be used routinely [13]. Second, the majority of clinical metabolomic profiling studies for early cancer diagnostics have been performed using small samples sizes that result in inadequate statistical power and validity [14]. To be clinically useful, these studies would need to be performed using large sample sizes in order to validate their utility. Last, quality control measures need to be standardized and implemented; slight differences in interlaboratory reproducibility of sample procurement and handling, data processing and statistical analysis, and interpretation and validation can skew the results of this highly analytical procedure, especially as significant intracellular changes in metabolite concentrations can occur quickly during biopsy procurement [14].

5. Expert opinion

With the recognition of the power of metabolomics and precision medicine in general, the use of metabolomic profiling for biomarker discovery and validation in cancer diagnostics will continue to increase. In fact, to increase the power of omics, there is a movement toward integrating several omics endeavors; for example, combination of proteomic and metabolomic data in renal cell carcinoma has allowed in depth analysis of altered metabolic pathways, resulting in identification of novel therapeutic targets that may not have been discovered through use of one omics technology alone [5].

In addition to solving the aforementioned limitations, it is essential to validate potential metabolic biomarkers and pathways in large cohorts in light of the very high bar needed to attain a clinically useful population screening biomarker. While metabolite discovery is clearly more exciting than validation, more effort needs to be focused toward translation of those findings. It is unclear if early stage metabolic changes in cancer will ever be able to provide indicators that can be identified through noninvasive biofluid, or even tissue biopsy samples, which are sensitive and specific enough to differentiate between cancer and noncancerous in a large group of asymptomatic individuals. Current biofluid or tissue analyses may find metabolites that differ between cancerous and noncancerous tissue, however, they may be general tumor proliferation biomarkers that cannot unambiguously identify a specific cancer. As many cancers share similar metabolic abnormalities, these common characteristics may end up complicating the ability to accurately differentiate among different types of cancers.

In conclusion, use of metabolomic profiling for detecting early cancer is promising in theory; however, many more obstacles remain to be overcome in order to discover its true potential in the clinic.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

RH Weiss is supported by U.S. Department of Health and Human Services, National Institutes of Health (1R01CA135401-01A1, 1R03CA181837-01).