Can Insulin Like Growth Factors Be Used As A Biomarkers Of Oral Cancer?-A Systematic Review

Keywords

Oral Cancer; IGF; IGFBP; Serum; Saliva.

Introduction

Globally, cancer is one of the leading causes of death accounting for approximately an estimated 10 million deaths in 2020.[1] Oral cancer, which is the growth of malignant cells in the oral cavity (lips, mouth and tongue) is associated with significant morbidity and mortality.[2] Oral cancer is the sixteenth most prevalent cancer worldwide, according to the GLOBOCAN 2020 survey, with 377,713 new cases (2.0 %) and 177,757 deaths (1.6%) in 2020.1 Oral cancers are highly frequent in South Central Asia which includes India, Sri Lanka, and Pakistan, reflecting the popularity of aka chewing (smokeless tobacco) and betel quid without tobacco in these countries.[3, 4] According to GLOBOCAN 2020, cancers of the lip and oral cavity are the leading cause of cancer death among men in India.[1]

Due to the increased burden of cancers, including oral cancer, investigation of molecular pathways associated with it and the identification of novel therapeutic targets have become the need of the hour. Circulating insulin-like growth factor (IGF) has a significant role in tissue growth and development and has been shown to be associated with cancers.[5, 6] IGF plays a key role in controlling cell proliferation, inhibiting apoptosis, differentiation, metabolism, angiogenesis and metastatic activities in various cancers.[ 7] The IGF family encompasses insulin and two IGF-1 and IGF-2, their related receptors (IGFR-1 and -2), six IGF-binding proteins (IGFBPs), and IGFBP proteases.[8] Numerous studies have suggested that the IGF family plays a significant role in different malignancies such as colorectal [9], breast [10], ovarian [11], prostate cancer [12] pancreas [13], esophagus [14], stomach [15] and several others, but evidence related to oral cancers are limited. Serum IGF levels have been shown to be a potential diagnostic biomarker to detect early-stage of certain cancers.[16, 17] To our knowledge there are few studies that have examined the utility of serum IGF levels as a promising biomarker in the diagnosis/ prognosis of oral cancer. In addition, the use of salivary IGF levels as noninvasive biomarkers for diagnosis/prognosis of oral cancer is also not clear. Therefore, the purpose of this is to systematically review the available literature reporting on circulating serum/salivary IGF levels and its association with oral cancer.

Materials and Methods

Focussed question

Can serum or salivary IGF-1/IGFBP-3 be used a biomarker to evaluate the risk of oral cancer?

Study Selection Criteria

The following criteria were used to select the studies to be included in the study:

• Studies designed to measure the levels of any of the IGF family members in only oral cancer patients

• Studies which utilized only salivary and serum samples for the measurement

• Studies should be in the English language

Search Strategy

A systematic search was carried out using the electronic databases (PUBMED, Science direct, Embase) for clinical studies which measured IGF in patients with oral cancer. The key words used in the search builder were Insulin-like growth factor, Insulin-like growth factor-1, Insulin-like growth factor-2, IGF-1, IGF-2, Insulin like growth factor binding proteins, IGFBP-3, IGFBP-1, IGFBP-2, Oral cancer,Oral squamous cell carcinoma,Salivary biomarkers and Serum Biomarkers. Manual search of the main journals of oral oncology and maxillofacial surgery was also done. All titles and abstracts of all the articles were analysed by the author.

Outcome Measures

IGF-1 Measurements: IGF-1 values measured from saliva and serum samples by ELISA,IRMA,Chemiluminisence methods reported in ng/ml and pg/ml

IGFBP-1,2,3- IGF-1 values measured from saliva and serum samples by ELISA methods reported in ng/ml orpg/ml

Data Extraction

Following the search, all the returned articles were assessed based on their title and abstracts and were included if they met the inclusion criteria.The included articles were assessed completely and the data was represented in tables. Data pertaining to the author name, year of publication, study type, biomarkers analysed, source of markers, level of markers, conclusions, limitations were extracted from the articles.

Quality Assessment

All articles were subjected to a quality assessment checklist put forth by the National Heart,Lung and Blood Institute (NIHLB). [18] The checklist is a 12 point list for assessing case control studies. Level of evidence of all the articles were determined using the Oxford centre of evidence based medicine criteria.[19]

Results

The electronic search initially returned 115 articles.Following title and abstract review, 95articles were excluded from the list.After full review of the remaining 20 articles, a total of 4 articles were identified for inclusion in the review and a data extraction was performed for them.(Figure 1)

Out of the 4 includedarticles, only one article measured the salivary values of IGF-1 in oral cancer patients.[20] The rest of the articles measured the circulating levels of IGF-1 and its binding proteins.[21-23] Table 1summarizes the characteristics, methods, results and conclusions of the 4 selected articles.

Studies measuring Salivary IGF-1

Only one study has measured the salivary levels of IGF-1.20 25 subjects with OSCC and 25 healthy subjects were included as controls. The values were measured using enzyme-linked immunosorbent assay (ELISA).

Studies measuring Serum IGF-1 and IGFBP

The serum levels of IGF-1 and IGFBP were assessed in three studies. [21-23] These studies included a total of 158 subjects with oral squamous cell carcinoma and 109 healthy subjects as controls. The values of IGF-1 and its binding proteins were analysed by using immuno-radiometric assay (IRMA), enzyme-linked immunosorbant assay (ELISA) and a Chemiluminescence Immunoassay.

IGF-1 Levels

All the 3 studies that measured the circulating levels of IGF-1 have reported that the levels are lesser with respect to the control group. This data was statistically significant in two of the three studies (Table 2). Shpitzer et al., reported that the salivary concentrations of IGF-1 was found to be 117% higher than the controls and was also statistically significant.[20]

IGF binding proteins

Only two studies have measured IGF binding proteins.[22, 23] The mean IGFBP-1 and IGFBP-2 in plasma were significantly higher in OSCC patients than in the healthy controls. IGFBP-3 was found to be significantly higher in the controls when compared to the OSCC group(Table 2).

IGF-1 and IGFBP-3 Correlation

One study which measured both IGF-1 and IGFBP-3, found a strong positive co-relation between them, which was statistically significant.[23]

Survival levels

In tongue cancer patients, when the IGF-1 levels were <50.0 ng/ ml,the mean survival in months was 14.16 ± 1.08 and when the levels were>50.0 ng/ml, it was 13.83 ± 2.37, which was non-significant.[ 21] Similarly, OCSS patients with IGF-1 values <130 ng/ml showed a lower survival rate for 1 year (80.8%) compared to those with values =130 ng/ml(94.9%), which was statistically significant and IGFBP-3 values <3.1 µ/ml also indicated a lower survival rate (82.9%) compared to those with values =3.1 µ/ml (92.7%), however, the difference was not statistically significant.23The combined IGF-1 levels (<130 ng/ml) and IGFBP-3 levels (<3.1 µ/ml) had a substantially lower survival rates (78.5%) compared to those with combined values of =130 ng/ml and =3.1 µ/ml respectively.[23]

Quality assessment of the studies

Table 3 shows the quality assessment of all the included studies.

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Table 1:

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Table 1. Characteristics, results and conclusions of the selected articles.

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Table 2:

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Table 2. Insulin growth factor and Insulin growth factor binding protein levels in the selected studies.

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Table 3:

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Table 3. Quality Assessment of the studies.

Discussion

A systematic review of published studies on the relationship between serum/salivary IGF-I and IGFBP-3 levels and the risk of oral cancer was conducted. The data from the three studies which assessed the serum concentration have demonstrated that reduced levels of IGF-I and IGFBP-3 were linked with oral cancer. While the study which assessed the salivary levels reported that in individuals with oral cancer, salivary levels of IGF1 increased significantly compared to healthy controls.

IGF’s are multifunctional peptides that have systemic and hormonal effects on cell activity, which are present in highlevels in the circulation.[24] Growth factors such as IGF-1 and IGF-2 are closely linked with development and growth of cancer. The IGF-1 receptor, which is involved in tumor-induced cell transformation, regulates the action of IGFs. These effects are dependent on IGF bioavailability, which is regulated by IGFBPs. IGF-I binds to the key IGF binding protein, IGFBP-3, in the circulation, and both of these proteins play distinct roles in normal somatic growth by fostering cellular proliferation and inhibiting apoptosis both in vivo and in vitro.[25] As tumors grow due to excessive growth and a lack of apoptosis, it could be postulated that both IGF-1 and IGFBP-3 significantly contribute in its development. Concentrations of IGF-I and IGFBP-3 differ significantly between individuals, which could influence the risk of cancer.

High circulating IGF-I concentrations have previously been linked to an increased risk of various cancers, while high IGFBP- 3 concentrations have been linked to a lower risk. [26-28] In most circumstances, IGFBP-3 inhibits IGF-mitogenic activity, and is thus inversely related to the risk of cancer.Serum levels of IGF-1 were found to be elevated in patients who had secondary primary tumors.[29] IGF-I and IGFBP-3 concentrations can be easily determined in both blood and saliva and can be useful in determining cancer risk.

Saliva is a very easily obtained, bio-specimen with a non-invasive sample collection method. As saliva is in close proximity to the site of the cancer, its role as a source of biomarkers is highly invaluable.[30] A recent study has diagnosed oral cancer from salivary metabolic profiling with a rate of 86.7% accuracy.[31] The utility of saliva as a diagnostic fluid cannot be understated. Many therapeutic strategies that target IGF signaling have been investigated in several cancers over the last few decades. Of late, monoclonal antibodies such as ganitumab, figitumumab and others have targeted the IGF-1 receptor to obstruct the binding of IGF-1 and thereby inhibiting the IGF-1 signaling pathway which in turn reduces cancer progression. This stresses the need for a reliable, non-invasive and cost effecting method to screen and identify patients with altered IGF levels so as to provide a better treatment option and a good quality of life. [32, 33]

Majority of the articles which we excluded were based on tissue analysis post-operatively, which was an exclusion criteria being in line with the aim of the study. All of the excluded articles which have reported on the tissue levels of IGF-1 and its binding proteins have observed an over expression of the factors and have stated their role as a prognostic biomarker.Studies which included other head and neck squamous cell carcinomas were also excluded. This review has its own limitations.In the four articles, a total of three techniques were utilized to measure the values of IGF-1 and its binding proteins. This caused us to doubt as to whether these values can be taken together to be compared. Also a meta-analysis could not be done as only two articles mentioned the values, while for one study it was calculated from the available data and the other article represented the values in percentage. The inclusion criteria adopted by us could also have resulted in the reduced number of articles.

As evident from our systematic review, research involving the salivary and serum IGF-1 concentration and its binding proteins are very few with respect to oral cancers. We were able to find only four articles which studied them, but all four of them used a different methodology to measure the values. A well-designed prospective studies based on salivary samples which can clearly identify the biological action of IGF-1 in oral cancers are needed. Case-control studies of larger number of patients are also required to identify the possibility of whether IGF-1 and IGFBP-3 may be utilized as a valid diagnostic and prognostic marker for oral cancer.

Conclusion

With the availability of limited data, the role and utility of salivary and serum IGF-1 and IGFBP-3 as prognostic biomarkers in oral cancer patients cannot be assessed. More clinical studies designed and standardized to measure the values of IGF with a long term follow up of the patients will give a more clearer picture of the actual role of IGF-1 and its binding proteins role in oral cancer.