Abstract
Background:
Higher serum insulin-like growth factor 1 (IGF-1) has been linked to colorectal cancer (CRC), with evidence supporting increased risk for colon but not rectal tumors. Few studies have included substantial numbers of non-Hispanic Black individuals, who have elevated population-level CRC risk. We investigated associations between IGF-1 and CRC in the Southern Community Cohort Study. We also report associations with IGF binding protein 3 (IGFBP-3), the primary IGF-1 transporter, and the IGF-1/IGFBP-3 ratio (a surrogate marker for biologically available IGF-1).
Methods:
Participants with incident CRC (N=297) were individually matched with controls (N=604) on age, race, and sex. The majority of the cohort reports Black racial identity (75%). Serum IGF-1 and IGFBP-3 were measured at enrollment. Logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for CRC, colon and rectal cancers.
Results:
For higher IGF-1 (tertile 3vs1), the OR for CRC was 1.45 (CI 0.95-2.21). Higher IGF-1 was associated with greater odds for colon cancer (OR 1.64, CI 1.01-2.64) but not rectal cancer (OR 0.93, CI 0.43-1.97). The associations with CRC and colon cancer were consistent among participants who fasted prior to serum draw (N=356, CRC: OR 1.89, CI 0.95-3.78; colon cancer: OR 2.08, CI 0.96-4.51). No associations were observed for IGFBP-3 or the IGF-1/IGFBP-3 ratio in the full sample.
Conclusion:
Higher IGF-1 was associated with increased odds for colon cancer, but not rectal cancer, among predominantly non-Hispanic Black individuals with lower socioeconomic status, consistent with findings from predominantly non-Hispanic White cohorts.
Keywords: IGF-1, IGFBP-3, colorectal cancer, racial disparities
1. Introduction
Colorectal cancer (CRC) is the fourth most common cancer in the United States (US) [1]. It is estimated that there will be more than 154,000 new cases of CRC in the US in 2025 [1]. Elevated serum insulin-like growth factor 1 (IGF-1) is implicated in the development of CRC, as the cell-surface receptor for IGF-1 is overexpressed in CRC compared to healthy gastrointestinal epithelium [2]. IGF-1 is structurally similar to insulin and promotes tumor growth by binding either the insulin receptor or IGF-1 receptors on target cells [3]. Several epidemiological studies show higher risk for CRC among individuals with an elevated level of serum IGF-1 [4-6], whereas other groups find no association [7-12]. Moreover IGF-1’s influence may vary by cancer site. A meta-analysis of case-control studies supports an association between the highest quantile of IGF-1 with risk for colon cancer (odds ratio 1.35, 95% confidence interval 1.04-1.79) [13], but not rectal cancer (odds ratio 0.88, 95% confidence interval 0.57-1.35). Other research from the EPIC cohort showed an association between IGF-1 and colon cancer among participants less than < 55 years at blood draw.
The biological activity of IGF-1 may be modified by IGF binding protein 3 (IGFBP-3), which binds approximately 85% of circulating IGF-1 [14]. Higher levels of IGFBP-3 may reduce the risk for CRC by preventing the interaction between IGF-1 and its target receptor [15]. A majority of studies report no association between serum IGFBP-3 and risk for CRC [8,11-13,16-19], although a minority report an inverse association [4,5,10].
Few epidemiological studies of serum IGF-1, IGFBP-3 and risk for CRC include large numbers of non-Hispanic Black individuals [20]. Notably, there are significant racial disparities for CRC, as individuals identifying as non-Hispanic Black have 17% higher risk for incident CRC compared to non-Hispanic White individuals [21]. To ensure that epidemiological research findings generalize to populations with higher underlying risk for CRC, it is necessary to perform studies comprised of a more diverse sample. Consequently, we performed a nested case-control analysis within the Southern Community Cohort Study (SCCS), a longitudinal study which includes large numbers of non-Hispanic Black individuals designed to investigate causes of racial disparities [22].
2. Materials and methods
2.1. Study sample
Data arise from a nested case-control study within the SCCS. In total, approximately 85,000 English speaking participants (age 40-79 years) were enrolled in the SCCS between 2002-2009. Eighty-six percent of participants were recruited via community health centers, and 14% were recruited via general population mailings and telephone calls. At enrollment, participants completed questionnaires concerning their demographic background, lifestyle risk factors, medical history, current medication use, family history of disease, cancer screening, typical diet, and use of dietary supplements. Body mass index (BMI, kg/m2) was determined from participant height and weight obtained from medical records when available or via height and weight self-reported on questionnaires. Forty-six percent of SCCS participants consented to provide a serum sample at enrollment. Only participants recruited from community health centers were able to provide a serum sample. Additional information about the SCCS study design, recruitment, and questionnaires has been previously published [22,23]. The Institutional Review Boards of Vanderbilt University Medical Center and Meharry Medical College provided approval for this study. All participants provided written informed consent and all study procedures conformed to the Declaration of Helsinki.
2.2. Identification of incident colorectal cancer cases and controls
Incident cases of CRC were identified via linkage with state cancer registries and the National Death Index utilizing the following International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) codes: C180-C189, C199, and C209. Tumors of the colon (including the proximal and distal regions) included ICD-O-3 codes C180-C189, while tumors of the rectum or rectosigmoid junction included codes C199 and C209. Information on tumor stage at diagnosis was also obtained from the state registries, utilizing the tumor, node, and metastasis staging system (American Joint Committee on Cancer, Seventh Edition) [24]. Follow-up for incident CRC was complete through 2016-2020, depending on the registry. In total, there were 338 participants who provided a serum sample at enrollment and later were diagnosed with incident CRC. Each participant with incident CRC was individually matched with two control participants based on age at enrollment (in five-year groups), race, and sex.
2.3. Measurement of serum biomarkers
The concentrations of serum total IGF-1 and IGFBP-3 were determined using commercially available enzyme linked immunosorbent assays (ELISAs) from Diagnostic Systems Laboratories, Inc. (DSL; Webster, TX). The total IGF-1 (DSL kit #10-2800, Research Resource Identifier (RRID): AB_3697970) and IGFBP-3 (DSL kit #10-6600, RRID: AB_3698064) assays were conducted in specific accordance with the manufacturer’s recommendations. Each serum sample was tested in duplicate and the mean value was used as the result. Samples with disparate values (>10% coefficient of variation (CV)) were repeated. Plates with quality control samples that had values outside the expected range were repeated. For IGF-1, the manufacturer previously reported intra-assay CVs of 4-8% and inter-assay CVs of 3-6% for three samples [25]. For IGFBP-3, the intra- and inter-assay CVs ranged from 7-9% and 8-11%, respectively [26].
2.4. Exclusion criteria
Participants were excluded who self-reported having a previous cancer diagnosis (excluding non-melanoma skin cancer) at SCCS enrollment (N = 69) or who had missing data for IGF-1 or IGFBP-3 (N = 40). The final analysis included 297 participants with incident CRC and 604 matched controls.
2.5. Statistical analysis
The distribution of sample characteristics, including sociodemographic characteristics and lifestyle risk factors for CRC, were tabulated for the full sample and by case/control status. Spearman correlation coefficients were calculated to determine the pairwise associations between all biomarkers. Unconditional logistic regression modeling was utilized to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for CRC by tertile of IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 ratio, and per one standard deviation (SD) increase in each exposure. Unconditional logistic modeling may improve precision relative to the conditional model in studies where there are fewer matching variables, without increasing risk for bias [27]. Adjustment for matching variables in the unconditional logistic model is required to mitigate confounding [27]. Due to exclusions, there were 55 participants without a match, and 29 cases that were matched to one control only. Tertile cut points were determined from the distribution among control participants only. The minimally adjusted model was adjusted for matching factors including enrollment age (in 5-year categories), race, (Black, White, Other), and sex (male, female). The risk factor adjusted model was further adjusted for additional sociodemographic characteristics and CRC risk factors measured at enrollment including education (did not complete high school, high school graduate, post-high school education), BMI (< 25.0, 25.0-29.9, 30.0-34.9, ≥ 35.0 kg/m2), diabetes status (yes/no), insurance coverage (yes/no), smoking status (never, former, current), heavy alcohol consumption (≥ 1 drink/day for females, ≥ 2 drinks/day for males, yes/no), CRC screening at enrollment (sigmoidoscopy or colonoscopy, yes/no), physical activity (meeting guidelines, yes/no [28]), annual household income (<$15,000, $15,000-49,999, ≥$50,000), and family history of CRC (yes/no). Because similar estimates were obtained for the minimally adjusted and risk factor adjusted models, results from the minimally adjusted model are not presented. The fully adjusted model included all variables from the risk factor adjusted model with mutual adjustment for IGF-1 and IGFBP-3. The association between serum biomarkers and incident CRC was measured for the full sample and for the subsample of participants who reported fasting at least eight hours prior to the serum draw. Associations were similar in the subsample of fasted participants as compared to the full sample. Polytomous logistic regression was utilized to obtain separate estimates for colon and rectal tumors using data from the full sample. Further, we tested for interactions between serum biomarkers and sex (male, female), race (Black, White), annual household income (<$15,000, ≥$15,000), and CRC screening prior to enrollment (no, yes) by adding an interaction term to the fully adjusted model. P-interaction was calculated via the Wald test. Given the limited number of cases in the data set with early-onset CRC (diagnosed prior to age 50 years, N = 42), age-stratified analyses were not performed. To investigate the possible effect of undiagnosed tumors on serum levels of IGF-1, an additional sensitivity analysis was performed to exclude participants diagnosed less than one year after enrollment.
Approximately 1-2% of observations for covariates were missing. Missing values were imputed using the sex- and race-specific mode (categorical variables) or median (continuous variables). P < .05 was utilized as the threshold for statistical significance. All analyses were completed using SAS version 9.4 (SAS inc., Cary, NC) in the year 2024.
3. Results
3.1. Sample characteristics and distribution of tumor markers
A majority of participants were female (56%) and self-identified as Black (75%) (Table 1). Sixty-five percent of participants had household incomes less than $15,000 per year at enrollment. Approximately 40% of participants reported fasting for at least eight hours prior to blood draw. Among individuals diagnosed with CRC, the median age at enrollment was 55 years (interquartile range (IQR): 49-62 years), and the median age at CRC diagnosis was 59 years (IQR: 54-67 years). Compared to matched non-cancer participants, those who developed incident CRC were less likely to have household incomes greater than $15,000 per year, to have completed high school, to have insurance, or to have received screening for CRC prior to enrollment (Table 1). Participants with incident CRC were more likely to have a family history of CRC compared to controls (9% vs. 7%, respectively) and to self-report having diabetes at enrollment (31% vs. 23%, respectively).
Table 1:
Characteristics of colorectal cancer cases and matched controlsa
| Full sample (N = 901) |
Controls (N = 604) |
Cases (N = 297) |
|
|---|---|---|---|
| Enrollment age, median (IQR), years | 55 (49-62) | 55 (49-62) | 55 (49-62) |
| Sex | |||
| Female | 505 (56%) | 338 (56%) | 167 (56%) |
| Male | 396 (44%) | 266 (44%) | 130 (44%) |
| Race | |||
| Black | 678 (75%) | 454 (75%) | 224 (75%) |
| White | 200 (22%) | 135 (22%) | 65 (22%) |
| Other | 21 (2%) | 13 (2%) | 8 (3%) |
| Education | |||
| < High school grad | 323 (37%) | 196 (33%) | 127 (44%) |
| High school grad | 313 (36%) | 218 (37%) | 95 (33%) |
| Post-high school | 241 (27%) | 174 (30%) | 67 (23%) |
| Income | |||
| < $15,000/year | 553 (64%) | 361 (62%) | 192 (68%) |
| $15-49,999/year | 286 (33%) | 201 (34%) | 85 (30%) |
| ≥ $50,000/year | 29 (3%) | 22 (4%) | 7 (2%) |
| Insurance coverage | |||
| No | 364 (42%) | 234 (40%) | 130 (45%) |
| Yes | 506 (58%) | 349 (60%) | 157 (55%) |
| CRC screening at enrollment | |||
| No | 589 (68%) | 380 (66%) | 209 (73%) |
| Yes | 276 (32%) | 199 (34%) | 77 (27%) |
| CRC family history | |||
| No | 741 (92%) | 503 (93%) | 238 (91%) |
| Yes | 61 (8%) | 38 (7%) | 23 (9%) |
| BMI category (kg/m2) | |||
| < 25.0 | 204 (24%) | 135 (23%) | 69 (24%) |
| 25.0-29.9 | 256 (30%) | 169 (29%) | 87 (31%) |
| 30.0-34.9 | 199 (23%) | 141 (24%) | 58 (21%) |
| 35.0-39.9 | 119 (14%) | 83 (14%) | 36 (13%) |
| ≥ 40.0 | 89 (10%) | 57 (10%) | 32 (11%) |
| Smoking status | |||
| Never | 302 (34%) | 204 (35%) | 98 (34%) |
| Former | 240 (27%) | 154 (26%) | 86 (30%) |
| Current | 335 (38%) | 230 (39%) | 105 (36%) |
| Alcohol consumption | |||
| Light/moderateb | 734 (85%) | 494 (85%) | 240 (84%) |
| Heavyb | 131 (15%) | 86 (15%) | 45 (16%) |
| Meeting physical activity guidelines | |||
| No | 744 (85%) | 497 (85%) | 247 (85%) |
| Yesc | 128 (15%) | 86 (15%) | 42 (15%) |
| Sedentary time, median (IQR), hours/day | 8 (5.5-11) | 8 (6-12) | 7.2 (5-10.1) |
| HEI score 2010, median (IQR) | 58.5 (49.6-66.8) | 58.2 (48.9-66.4) | 59 (51.5-67.1) |
| Diabetes – enrollment | |||
| No | 649 (74%) | 450 (77%) | 199 (69%) |
| Yes | 226 (26%) | 136 (23%) | 90 (31%) |
| Age at diagnosis, median (IQR), years | - | - | 59 (54-67) |
| AJCC Tumor stage | |||
| 0-I | - | - | 71 (30%) |
| II | - | - | 60 (26%) |
| III | - | - | 40 (17%) |
| IV | - | - | 64 (27%) |
| Tumor location | |||
| Colon | - | - | 211 (75%) |
| Rectum | - | - | 70 (25%) |
Data presented as N (%) for categorical variables, and median (IQR) for continuous variables.
Light moderate/alcohol intake defined as ≤1 drink/day for women or ≤2 drinks/day for men. Heavy alcohol intake defined as > 1 drink/day for women or > 2 drinks/day for men.
Meeting physical activity guidelines defined as completing ≥ 75 minutes of vigorous or ≥ 150 minutes of moderate physical activity each week.
Abbreviations: AJCC – American Joint Committee on Cancer; BMI – body mass index; CRC – colorectal cancer; HEI – healthy eating index; IQR – interquartile range; MET – metabolic equivalent
3.2. Associations between IGF-1, IGFBP-3 and colorectal cancer
The mean [SD] serum concentrations for IGF-1 and IGFBP-3 were 94.6 [35.6] and 2522 [1245] ng/ml, respectively. The Spearman correlation coefficient for the pairwise association between serum IGF-1 and IGFBP-3 was 0.58 (P < .001).
There was a positive association between high IGF-1 and CRC risk, although OR per SD increase in IGF-1 was not statistically significant (OR = 1.14, 95% CI 0.95-1.37) (Table 2). IGF-1 modeled as a categorical exposure showed participants in the highest tertile for serum IGF-1 had OR of 1.45 (95% CI 0.95-2.21) compared to participants in the lowest tertile. Associations were strengthened among fasted individuals where higher IGF-1 was associated with higher odds for CRC in the linear model (OR 1.49, 95% CI 1.10-2.01 per one SD increase), and the highest tertile compared to the lowest tertile of IGF-1 resulted in an OR of 1.89 (95% CI 0.95-3.78).
Table 2:
Odds ratios (with 95% confidence intervals) for colorectal cancer by level of serum IGF-1 and IGFBP-3
| Full sample (N = 901) | 8-hour fasted (N = 356) | ||||||
|---|---|---|---|---|---|---|---|
| Marker | Cases / total (N) |
OR (95% CI) a |
OR (95% CI)b |
Marker | Cases / total (N) |
OR (95% CI) a |
OR (95% CI)b |
| IGF-1 (ng/ml) | IGF-1 (ng/ml) | ||||||
| T1 (11.0 – 74.9) | 84/285 | 1 (ref) | 1 (ref) | T1 (26.3 – 72.7) | 35/111 | 1 (ref) | 1 (ref) |
| T2 (75.2 – 101.5) | 99/300 | 1.17 (0.82-1.69) | 1.20 (0.83-1.74) | T2 (73.2 – 98.4) | 40/116 | 1.16 (0.64-2.13) | 1.25 (0.67-2.33) |
| T3 (101.6 - 274.8) | 114/316 | 1.36 (0.95-1.96) | 1.45 (0.95-2.21) | T3 (98.5 – 235.5) | 54/129 | 1.60 (0.89-2.85) | 1.89 (0.95-3.78) |
| Per 1-SD increase | 297/901 | 1.11 (0.96-1.28) | 1.14 (0.95-1.37) | Per 1-SD increase | 129/356 | 1.32 (1.03-1.67) * | 1.49 (1.10-2.01) * |
| IGFBP-3 (ng/ml) | IGFBP-3 (ng/ml) | ||||||
| T1 (312 - 1745) | 93/295 | 1 (ref) | 1 (ref) | T1 (619.9 – 1753) | 37/113 | 1 (ref) | 1 (ref) |
| T2 (1747 - 2893) | 94/295 | 1.02 (0.71-1.46) | 0.96 (0.66-1.40) | T2 (1760.2 – 3173) | 50/126 | 1.31 (0.74-2.32) | 1.02 (0.56-1.87) |
| T3 (2895 - 7987) | 110/311 | 1.15 (0.81-1.65) | 1.01 (0.66-1.54) | T3 (3196.2 – 7987) | 42/117 | 1.00 (0.55-1.84) | 0.59 (0.29-1.22) |
| Per 1-SD increase | 297/901 | 1.03 (0.89-1.20) | 0.95 (0.79-1.15) | Per 1-SD increase | 129/356 | 1.02 (0.80-1.30) | 0.81 (0.59-1.09) |
| IGF-1/IGFBP-3 ratio | IGF-1/IGFBP-3 ratio | ||||||
| T1 (0.01-0.03) | 92/293 | 1 (ref) | - | T1 (0.01 – 0.03) | 39/115 | 1 (ref) | - |
| T2 (0.03-0.05) | 99/301 | 1.04 (0.72-1.49) | T2 (0.03 – 0.04) | 38/113 | 1.01 (0.55-1.85) | ||
| T3 (0.05-0.18) | 106/307 | 1.20 (0.83-1.74) | T3 (0.04 – 0.16) | 52/128 | 1.42 (0.78-2.58) | ||
| Per 1-SD increase | 297/901 | 1.05 (0.91-1.22) | - | Per 1-SD increase | 129/356 | 1.17 (0.93-1.49) | - |
Risk factor adjusted model – Adjusted for age, race, sex, education, income, body mass index, diabetes status, insurance coverage, CRC screening at enrollment, smoking status, alcohol consumption, healthy eating index score, meeting physical activity guidelines, sedentary activity, and family history of CRC.
Fully adjusted model – Models are mutually adjusted for IGF-1 and IGFBP-3.
P-value < .05
Abbreviation: CI – confidence interval; CRC – colorectal cancer; IGF-1 – insulin-like growth factor 1; IGFBP-3 – insulin-like growth factor binding protein 3; OR – odds ratio
Importantly, the categorical analysis showed that participants in the highest tertile for IGF-1 (101.6–274.8 ng/ml) had higher odds for colonic tumors (OR 1.64, 95% CI 1.01-2.64) but not rectal tumors (OR 0.93, 95% CI 0.43-1.97) compared to participants in the lowest tertile. Associations were similar among fasted participants (colon: OR 2.08, 95% CI 0.96-4.51; rectum OR 1.22, 95% CI 0.34-4.35). The associations between serum IGF-1 and colon cancer were not modified by sex, race, annual household income, or screening for CRC (Supplementary Table S1). Similar results were observed for CRC (Figure 1).
Fig. 1.
Hazard ratiosa with 95% confidence intervals for colorectal cancer per 1-standard deviation increase in serum IGF-1 and IGFBP-3, stratified by sex, race, income, and screening for colorectal cancerb (N = 901)
a Analyses adjusted for age, race, sex, education, income, body mass index, diabetes status, insurance coverage, CRC screening at enrollment, smoking status, alcohol consumption, healthy eating index score, meeting physical activity guidelines, sedentary activity, family history of CRC, and IGF-1/IGFBP-3.
b CRC screening defined as self-reported colonoscopy or sigmoidoscopy completed prior to enrollment.
Abbreviation: CRC – colorectal cancer; IGF-1 – insulin-like growth factor 1; IGFBP-3 – insulin-like growth factor binding protein
The IGF-1/IGFBP-3 ratio was associated with increased odds of CRC among men (OR 1.25, 95% CI 1.00-1.55 per one SD increase), but not among women (OR 0.91, 95% CI 0.74-1.12) (p-interaction = .04) (Figure 1, Supplementary Table S1). A similar trend was observed for colon cancer (p-interaction = .11), as well as rectal cancer (p-interaction = .10). For CRC, the interaction was modestly strengthened among the subset of fasted participants (women: OR 0.85, 95% CI 0.60-1.21; men: OR 1.98, 95% CI 1.26-3.11, p-interaction = .004). The association between IGF-1/IGFBP-3 ratio and CRC was not modified by race, income, or CRC screening.
IGFBP-3 was not associated with CRC, colon or rectal cancer in the linear or categorical analyses (Tables 2 and 3). No differences in null association were observed in analyses stratified by race, sex, household income, or CRC screening (Figure 1, Supplementary Table S1).
Table 3:
Site-specific odds ratios (with 95% confidence intervals) for colon and rectal cancers by level of serum IGF-1 and IGFBP-3
| Colon cancer (N = 815) | Rectal cancer (N = 674) | |||||
|---|---|---|---|---|---|---|
| Marker | Cases / total (N) |
OR (95% CI) a |
OR (95% CI)b |
Cases / total (N) |
OR (95% CI) a |
OR (95% CI)b |
| IGF-1 (ng/ml) | ||||||
| T1 (11.0 – 74.9) | 55/256 | 1 (ref) | 1 (ref) | 23/224 | 1 (ref) | 1 (ref) |
| T2 (75.2 – 101.5) | 75/276 | 1.41 (0.93-2.12) | 1.45 (0.95-2.21) | 21/222 | 0.85 (0.44-1.63) | 0.82 (0.42-1.60) |
| T3 (101.6 - 274.8) | 81/283 | 1.52 (1.00-2.29)* | 1.64 (1.01-2.64)* | 26/228 | 1.01 (0.54-1.91) | 0.93 (0.43-1.97) |
| Per 1-SD increase | 211/815 | 1.11 (0.95-1.31) | 1.14 (0.93-1.40) | 70/674 | 1.05 (0.81-1.36) | 1.02 (0.73-1.41) |
| IGFBP-3 (ng/ml) | ||||||
| T1 (312 - 1745) | 60/262 | 1 (ref) | 1 (ref) | 27/229 | 1 (ref) | 1 (ref) |
| T2 (1747 - 2893) | 72/273 | 1.15 (0.76-1.73) | 1.09 (0.71-1.67) | 16/217 | 0.66 (0.33-1.30) | 0.64 (0.31-1.29) |
| T3 (2895 - 7987) | 79/280 | 1.25 (0.83-1.87) | 1.12 (0.69-1.80) | 27/228 | 1.00 (0.55-1.84) | 0.93 (0.44-1.94) |
| Per 1-SD increase | 211/815 | 1.04 (0.88-1.22) | 0.96 (0.78-1.17) | 70/674 | 1.06 (0.81-1.39) | 1.05 (0.75-1.47) |
| IGF-1/IGFBP-3 ratio | ||||||
| T1 (0.01-0.03) | 64/265 | 1 (ref) | - | 25/226 | 1 (ref) | - |
| T2 (0.03-0.05) | 79/281 | 1.25 (0.84-1.87) | 17/219 | 0.51 (0.26-1.02) | ||
| T3 (0.05-0.18) | 68/269 | 1.19 (0.78-1.82) | 28/229 | 0.92 (0.49-1.74) | ||
| Per 1-SD increase | 211/815 | 1.05 (0.89-1.23) | - | 70/674 | 1.02 (0.78-1.33) | - |
Risk factor adjusted model – Adjusted for age, race, sex, education, income, body mass index, diabetes status, insurance coverage, CRC screening at enrollment, smoking status, alcohol consumption, healthy eating index score, meeting physical activity guidelines, sedentary activity, and family history of CRC.
Fully adjusted model – Models are mutually adjusted for IGF-1 and IGFBP-3.
P-value < .05
Abbreviation: CI – confidence interval; CRC – colorectal cancer; IGF-1 – insulin-like growth factor 1; IGFBP-3 – insulin-like growth factor binding protein 3; OR – odds ratio
3.3. Sensitivity analysis
Participants with incident CRC diagnosed less than one year after blood draw had higher mean [SD] serum IGF-1 (109.7 [40.6] ng/ml) compared to participants diagnosed more than one year after blood draw (94.2 [35.3] ng/ml) (Supplementary Table S2). After excluding 39 participants diagnosed less than one year after blood draw, the association between high serum IGF-1 and CRC in the fully-adjusted model was similar compared to the full sample (OR 1.53, 95% CI 0.98-2.38, tertile 3 vs. 1) (Supplementary Table S3). Further, participants in the highest tertile for the IGF-1/IGFBP-3 ratio had higher odds for CRC (OR 1.55 95% CI 1.04-2.30).
4. Discussion
In brief, we identified an association between higher serum IGF-1 and elevated risk for colon cancer, but not rectal cancer, in a cohort of predominantly non-Hispanic Black individuals. This study adds to a body of evidence linking IGF-1 to site-specific risk for colon cancer. After adjusting for risk factors and serum IGFBP-3, participants in the highest tertile of serum IGF-1 had an estimated 64% higher risk for colon cancer compared to the participants in the lowest tertile, but no difference in risk is observed for rectal cancer. In stratified analyses, the association between IGF-1 and colon cancer was not modified by sex, race, or socioeconomic status.
Notably, IGFBP-3 is positively correlated with IGF-1, likely reflecting the regulatory effect of growth hormone on the expression of both proteins by the liver [29]. Higher levels of IGF-1 may mask the potential protective effects of IGFBP-3, while higher IGFBP-3 may interfere with the binding of IGF-1 to target tissue receptors [3]. Consequently, mutual adjustment has been a common approach to identify potential independent effects of these biomarkers on CRC risk [9,10,30].
The finding of increased risk for colon but not rectal tumors may reflect a site-specific association for IGF-1, although imprecise estimates due to limitations in sample size prevent firm conclusions about the impact of tumor location. However, a site-specific association is consistent with results from a meta-analysis by Chi et al. (2013), who reported that participants in the highest quantile of IGF-1 exposure had 35% greater odds for colon cancer (95% CI 1.04-1.75) [13], while no association was observed for rectal cancer (OR 0.88, 95% CI 0.57-1.35). The biological factors underlying this potential site-specific association are not clear. The colon and rectum have distinct embryological origins, blood supplies, and tumor characteristics [31]. One possibility is that the autocrine and paracrine effects of locally produced IGF-1 play a larger role for rectal tumors. In support of this, Vrieling et al. reported that IGF-1 mRNA in healthy tissue samples increased progressively from the ascending colon to the rectum [32].
Immunohistochemical analysis has confirmed that the IGF-1 receptor is significantly overexpressed in colon cancer tumor tissue compared to the healthy gastrointestinal epithelium [2], suggesting that tumors depend on IGF-1 signaling for growth and survival. Further, the epidemiological associations between serum IGF-1 and colon cancer risk are supported by a body of histological and experimental evidence demonstrating the mitogenic and pro-tumorigenic effects of IGF-1 in the colon [3]. IGF-1 binds to the IGF-1 receptor to activate multiple mitogenic and anabolic signaling pathways linked to tumor development, including the PI3K/AKT/mTOR and mitogen-activated protein kinase pathways [33,34]. In mice with diet-induced obesity, IGF-1 treatment increased the growth of colon cancer cell allografts, leading to larger tumor end volume compared to control animals [35]. In another mouse study, Cao et al. (2013) reported that IGF-1 stimulated tumor vascular endothelial growth factor (VEGF) expression, leading to higher rates of tumor angiogenesis and metastasis [36]. In vitro studies demonstrate that IGF-1 directly stimulates proliferation of colon cancer cell lines and inhibits apoptosis [37-39]. IGF-1 also supports the cellular uptake of glucose via binding to the insulin and IGF-1 receptors, providing adenosine triphosphate (ATP) to support cell mitosis and anabolism required for tumor growth [3].
We did not observe an association between CRC and IGFBP-3. IGFBP-3 is the dominant IGF-1 binding protein and facilitates IGF-1 transport from the liver to target tissues [14]. It has been hypothesized that higher levels of IGFBP-3 may protect against CRC by reducing the amount of ‘free’ IGF-1 available to interact with its receptor [14]. Although several earlier studies reported a protective association between IGFBP-3 and CRC [4,5,10,40], other studies have generally found no association with risk [7,9,11,12,16-19,30,41-44]. In part, these apparently contradictory findings may be explained by inconsistent adjustment for IGF-1, which is highly correlated with IGFBP-3 [8]. Further, the expression of multiple IGFBPs and their interaction with IGF-1 and IGF-II can be influenced by physiological states including obesity and diabetes [3], creating a complex system that may have unpredictable effects on cancer development. In agreement with our findings, results from a previous meta-analysis showed no association with IGFBP-3 [13]. Currently, there is little evidence that IGFBP-3 is a useful marker of CRC risk.
A sex-specific association was observed for the association between the IGF-1/IGFBP-3 ratio and CRC among men only (HR 1.25, 95% CI 1.00-1.55 per one SD increase) with modest statistical evidence for interaction (p-interaction = .04). It has been proposed that this ratio may better capture the amount of ‘free’ (i.e. unbound) IGF-1 that is available to interact with its receptor in the gastrointestinal epithelium [45]. It is possible that the lack of association among women reflects anti-tumorigenic effects of serum estradiol (E2) in the gastrointestinal epithelium [46]. In support of this, E2 has been reported to enhance DNA mismatch repair, promote cell-cycle arrest, and increase apoptosis in vitro and in murine models of CRC [47,48]. However, other studies that were limited to male participants did not find an association between the IGF-1/IGFBP-3 ratio and CRC risk, including the Shanghai Cohort Study [17] and the Alpha Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study [8]. Conversely, Wei et al. (2005) reported that a higher ratio was associated with significantly elevated risk for CRC among women from the Nurses’ Health Study [41]. Additional research is required to clarify whether the associations for serum IGF-1, IGFBP-3 and the IGF-1/IGFBP-3 ratio are sex-specific.
Our study has several limitations. First, while we attempted to control for the post-prandial release of IGF-1 by performing a subgroup analysis of fasted participants, only 40% of participants were fasting at least eight hours prior to their blood draw. Consequently, the estimates obtained for this subgroup analysis are less precise than for the full sample. Further, given that most participants with incident CRC were diagnosed less than ten years after completing their blood draw, it is possible that undiagnosed tumors influenced serum IGF-1 levels. However, we found that associations were similar after excluding those who were diagnosed less than one year after enrollment. Finally, given the unique demographic characteristics of the SCCS sample, it is possible that the results may not generalize to samples with higher socioeconomic status. Further, our sample had a high proportion of participants identify as female (56%), consistent with the larger SCCS cohort [23], possibly reflecting the higher propensity for females to participate in research and to access healthcare [49]. Strengths of our study include that the SCCS is enriched for participants identifying as non-Hispanic Black, a population that is underrepresented in epidemiological research. Further, the SCCS collected detailed information concerning demographic and lifestyle risk factors on enrollment questionnaires, which allowed us to adjust for multiple potential confounding variables, including smoking status, diet, and physical activity.
4.1. Conclusions
In conclusion, the present study adds to a body of evidence linking higher IGF-1 to elevated risk for colon cancer, but not rectal cancer. To the authors’ knowledge, this is the first such study that included a cohort of predominantly non-Hispanic Black participants with lower socioeconomic status, indicating that this finding generalizes to a population with elevated risk for CRC that is underrepresented in epidemiological research. Additional research is required to determine whether pharmaceutical or lifestyle interventions to reduce IGF-1 exposure are useful strategies to mitigate risk for colon cancer.
Supplementary Material
Highlights.
Higher serum IGF1 was linked to higher odds for colon cancer, but not rectal cancer
Serum IGF binding protein 3 was not related to odds for colon or rectal cancer
A higher IGF1/IGFBP3 ratio was linked to higher odds for colon cancer in men only
Acknowledgements:
Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. Cancer data for SCCS cancer cases from West Virginia have been provided by the West Virginia Cancer Registry. The opinions expressed are those of the authors and do not necessarily represent those of the CDC or the West Virginia Cancer Registry. Data collection and sample preparation were performed by the Survey and Biospecimen Shared Resource which is supported in part by the Vanderbilt-Ingram Cancer Center (P30CA68485).
Funding:
This work was supported by the National Cancer Institute at the National Institutes of Health (grant number R00 CA207848 to S Warren Andersen); the University of Wisconsin-Madison, Office of Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation and the University of Wisconsin Carbone Cancer (grant number P30 CA014520 to HH Bailey). The Southern Community Cohort Study (SCCS) is supported by the National Cancer Institute at the National Institutes of Health (grant number U01 CA202979 to W Zheng), including special allocations from the American Recovery and Reinvestment Act (grant number 3R01 CA092447-08S1 to WJ Blot). The funding source had no role in the study design, in the collection, analysis, and interpretation of data, or in the decision to submit the article for publication.
Abbreviations:
- BMI
body mass index
- CI
confidence interval
- CRC
colorectal cancer
- IGF-1
insulin-like growth factor 1
- IGFBP-3
insulin-like growth factor binding protein 3
- OR
odds ratio
- SCCS
Southern Community Cohort Study
Footnotes
Declaration of interests: None
Ethics approval: The Institutional Review Boards of Vanderbilt University Medical Center and Meharry Medical College provided approval for this study. All study procedures conformed to the Declaration of Helsinki.
Consent to participate: All participants provided written informed consent.
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Data availability:
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
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Associated Data
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Supplementary Materials
Data Availability Statement
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.