Abstract
Background/Aim
Expression of the gene encoding collagen type I α1 chain (COL1A1) in cancer tissue primarily results in production of the pro-form of COL1A1, which can be released into the bloodstream. This study aimed to investigate whether plasma levels of pro-COL1A1 are associated with clinicopathological characteristics and long-term survival in patients with colorectal cancer (CRC).
Materials and Methods
Plasma levels of pro-pro-COL1A1 were measured in 148 patients with CRC and 28 healthy controls using an enzyme-linked immunosorbent assay (ELISA).
Results
Plasma levels of pro-COL1A1 were significantly lower in patients with CRC compared with healthy controls (p<0.001). Lower levels were also observed in men compared with women. Kaplan-Meier survival analysis demonstrated that a low plasma level of pro-COL1A1 was associated with poorer overall survival considering the entire cohort, as well as in subgroups of patients with colon cancer, depth of tumor invasion T3+T4, node-negative (N0) disease and in females.
Conclusion
These findings suggest that plasma levels of pro-COL1A1 may serve as a prognostic biomarker for long-term survival in patients with CRC.
Keywords: Collagen type I α1 chain, COL1A1, clinical parameters, prognostic factor, biomarker, colorectal cancer
Introduction
Colorectal cancer (CRC) is one of the most common malignancies and a leading cause of cancer-related mortality worldwide (1). Although the precise mechanisms underlying colorectal carcinogenesis are not fully understood, tumor initiation and progression involve multiple genetic and epigenetic alterations that are closely linked to inflammatory processes (2, 3). Inflammatory mediators such as interleukins and chemokines, produced either by tumor cells or by leukocytes within the tumor microenvironment (TME), contribute to CRC progression and metastasis by promoting tumor growth, angiogenesis, and immune modulation (4). The extracellular matrix (ECM) is a major component of the TME, alongside tumor, stromal, and immune cells. Alterations in ECM composition and structure modulate key hallmarks of cancer and play a crucial role in tumor progression, metastasis, and response to anticancer therapies (4, 5). Collagens are the principal structural components of the ECM. Under normal physiological conditions, collagen homeostasis is maintained through a tightly regulated balance of synthesis, degradation, and post-translational modifications that preserve tissue integrity. In tumor tissue, however, this balance is disrupted resulting in substantial alterations in ECM composition (5).
Type I collagen, the most abundant ECM protein, consists of two α1 chains and one α2 chain forming a triple-helical structure. These chains are encoded by the COL1A1 and COL1A2 genes located on chromosomes 17 and 7, respectively (6, 7). COL1A1 exhibits oncogenic activity and is highly expressed in multiple cancer types. It regulates key cellular processes, including proliferation, metastasis, and apoptosis, and is closely associated with tumor progression and patient prognosis (6, 7). In CRC, COL1A1 has been shown to promote cancer cell migration through activation of the Wingless-Int/planar cell polarity (WNT/PCP) signaling pathway (8). Cancer-associated fibroblasts are a major source of type I collagen within the TME and actively contribute to ECM remodeling and tumor progression (5, 9). In healthy tissue, continuous ECM remodeling maintains tissue integrity and function through a balance between the synthesis of new ECM components, such as collagens, and the enzymatic degradation of older proteins. During cancer progression, this balance is disrupted, leading to dysregulated ECM remodeling. Cancer cells are known to secrete elevated levels of matrix metalloproteinases, which actively remodel and degrade the ECM. Such remodeling can generate degradation products that exert both pro- and anti-tumorigenic signaling effects (5, 6, 9).
Cleaved and modified collagen type I fragments, including N- and C-terminal propeptides, are released from the tissue into the bloodstream. It has been proposed that levels of fragments derived from collagen type I in blood reflect the dynamics of ECM synthesis and degradation (10). Consistent with this, several studies have demonstrated that markers of collagen turnover are associated with disease progression and prognosis in breast cancer, CRC and lung cancer (11-14).
In the present study, we aimed to investigate the plasma level of pro-COL1A1 in patients with CRC and evaluated their association with clinical characteristics and long-term survival.
Materials and Methods
Plasma samples from patients and controls. Blood samples from 148 patients with primary colorectal adenocarcinoma were collected between June 2010 and December 2016 at the Department of Surgery, Ryhov County Hospital, Jönköping, Sweden. Samples were obtained at the time of surgery from patients according to availability in strict chronological order. Clinical and pathological data were prospectively recorded in a dedicated database. Follow-up for overall survival (OS) continued until death or May 2023. Tumors were classified according to the American Joint Committee on Cancer classification system (15). The clinicopathological characteristics of the patient cohort are summarized in Table I.
Table I. Clinicopathological characteristics of 148 patients with colorectal cancer included in the study.
*Clinical data were not available for all patients. TNM: Tumor, node, metastasis.
The control group consisted of blood donors (n=28) recruited at Ryhov County Hospital from the same geographical region, with no known history of CRC. This cohort included 13 males and 15 females, with a median age of 53 years (range=27-66 years). All blood samples were centrifuged to separate plasma and stored at −70°C until analysis.
The study was approved by the Regional Ethical Review Board in Linköping, Sweden (Dnr. 2013/271-31) and written informed consent was obtained from all participants. All procedures were conducted in accordance with relevant guidelines and regulations and the Declaration of Helsinki.
Quantification of pro-COL1A1 in plasma. Plasma levels of pro-COL1A1 were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (#DPCA00; Bio-Techne, Abingdon, UK) in accordance with the manufacturer’s instructions. Concentrations in plasma from patients and controls are expressed as ng/ml; the limit of detection was 3.5 pg/ml. All measurements were performed in duplicate.
Statistical analysis. Comparisons of plasma levels of pro-COL1A1 between groups were performed using the Mann-Whitney U-test. OS was analyzed using the Kaplan-Meier method, and differences between survival curves were evaluated with the log-rank test. Cox proportional hazards regression analysis was used to assess the association between plasma levels of pro-COL1A1 and OS.Statistical analysis was conducted using Stata Statistical Software, Release 15 (Stata Corp LLC, College Station, TX, USA) and SPSS Statistics for Windows, version 14.0 (SPSS Inc., Chicago, IL, USA). All statistical tests were two-sided, and p<0.05 was considered statistically significant.
Results
Plasma levels of pro-COL1A1 and clinical characteristics. Plasma levels of pro-COL1A1 were quantified by ELISA and analyzed in relation to clinical characteristics. There were no significant differences in pro-COL1A1 according to clinical parameters with the exception of age and sex (Table II). Plasma levels of pro-COL1A1were significantly higher in females compared with males (p=0.024) and in patients younger than 74 years compared with those aged ≥74 years (p=0.015). Compared with healthy controls, patients with CRC exhibited a 35% lower plasma level of pro-COL1A1 (patients: median=62.8 ng/ml, range=21.4-159.4 ng/ml; controls: median=96.2 ng/ml, range=36.1-384.9; p<0.001).
Table II. Plasma levels of pro-collagen type I α1 chain (pro-COL1A1) according to age and sex of 148 patients with colorectal cancer.
Data are the median (range).
Plasma levels of pro-COL1A1 and survival. Patients were dichotomized into high- and low-level groups based on the median plasma concentration of pro-COL1A1.Patients with a low plasma level of pro-COL1A1 exhibited significantly poorer OS compared with those with a high level (p=0.024; Figure 1). In a multiple regression analysis adjusting for covariates reported in Table I, a low plasma level of pro-COL1A1 remained significantly associated with an increased risk of death, with a hazard ratio of 2.10 (95% confidence interval=1.26-3.52, p=0.005). Subgroup analyses demonstrated that a low plasma level of pro-COL1A1 was consistently associated with poorer survival in females (p=0.035), in patients with T3+T4 disease (p=0.010), and in those with colon cancer (p=0.042) (Figure 2) or N0 disease (p=0.049) (Figure 3).
Figure 1.
Kaplan-Meier analysis showing overall survival in relation to the plasma level of pro-collagen type I α1 chain (pro-COL1A1) in patients with colorectal cancer (n=147) with known follow-up time. The plasma levels are divided into two groups, above (red) and below (blue) the median.
Figure 2.
Kaplan-Meier analysis showing overall survival in relation to the plasma level of pro-collagen type I α1 chain (pro-COL1A1) in subgroups in patients with colorectal cancer. Overall survival in subgroups by sex (A), depth of tumor invasion T1+T2 and T3+T4 (B), colon and rectum (C), and TNM stage I+II and TNM stage III+IV (D). The plasma levels are divided into two groups, above (red) and below (blue) the median. p-Values between the subgroups are shown to the right.
Figure 3.
Kaplan-Meier analysis showing overall survival in relation to the plasma level of pro-collagen type I α1 chain (pro-COL1A1) in subgroups in patients with colorectal cancer. Tumor differentiation high+medium and tumor differentiation poor (A), tumor size <4 cm and tumor size >4 cm (B), and lymph node status N0 and lymph node status N1+N2 (C). The plasma levels are divided into two groups, above (red) and below (blue) the median. p-Values between the subgroups are shown to the right.
In addition, stratified analyses across clinical parameters revealed significant survival differences between patients with low and high plasma levels of pro-COL1A1 according to sex (females vs. males: p=0.017), T-stage (T1+T2 vs. T3+T4, p=0.017), colon vs. rectum (p=0.009), TNM stage I+II vs. III+IV (p=0.013) (Figure 2), tumor differentiation high/medium vs. poor (p=0.023), tumor size ≥4 cm vs. <4 cm (p=0.039), and lymph node status N0 vs. N1+N2 (p=0.008) (Figure 3).
Discussion
Previous studies have shown that COL1A1 is upregulated in several tumor types and is involved in important cellular processes, such as proliferation, metastasis and apoptosis but also patient prognosis (6).
In CRC, COL1A1 has been shown to exert oncogenic effects by promoting cancer cell migration through activation of the WNT/PCP signaling pathway (8). Despite this, limited data exist regarding the clinical relevance of the level of circulating pro-COL1A1 in patients with CRC.
In the present study, we investigated the plasma levels of pro-COL1A1 and evaluated their association with clinical characteristics and prognosis in patients with CRC. We found that plasma pro-COL1A1 levels were significantly lower in patients with CRC compared with healthy controls. Additionally, lower levels were observed in male patients and in individuals older than 74 years.
Expression of COL1A1 primarily results in the synthesis of the pro-α1 chain, which undergoes post-translational processing, including cleavage of N- and C-terminal propeptides that may subsequently be released into the circulation (7, 10). Circulating COL1A1 fragments are thought to reflect collagen synthesis and degradation, and such markers of turnover have been associated with disease progression and prognosis in breast, colorectal, and lung cancer (11-14). Collagen turnover occurs in both healthy and malignant tissues; in cancer, this process may be amplified or dysregulated due to fibroblast activation and fibrotic remodeling (9). The reduced plasma levels of pro-COL1A1 observed in patients with CRC in our study may therefore reflect altered COL1A1 turnover within the TME, potentially resulting in reduced release of COL1A1-derived fragments into the circulation. However, further mechanistic and longitudinal studies are needed to clarify the underlying biological processes.
Sex-specific differences in fibrosis incidence may partly be explained by the influence of male and female sex hormones on collagen regulation (7). In our study, a sex-specific difference was observed in the plasma level of pro-COL1A1, with significantly lower levels detected in males than in females. This difference may be hormonally mediated. Estrogen has been postulated as a key regulator of fibroblast behavior by contributing to tissue homeostasis and enhancing COL1A1 synthesis through activation of the phosphatidylinositol-4,5-biphosphate 3-kinase (PI3K)/AKT serine/threonine kinase 1 (AKT) signaling pathway (16). Our results indicate that estrogen may be one of several factors that may influence fibroblast activity in CRC and thereby modulates the production of pro-COL1A1. In addition to hormonal regulation, age-related mechanisms may also affect collagen expression. Specificity protein 1 (SP1) is a transcription factor that promotes the expression of oncogenes involved in tumor survival, progression, and metastasis. SP1 is highly expressed in CRC and has been associated with poor prognosis (17). Previous studies have demonstrated that aging is associated with reduced binding of transcriptional activators such as SP1 to the COL1A1 promoter in human skin fibroblasts, resulting in downregulation of COL1A1 transcription (18). Consistent with these findings, we observed lower plasma levels of pro-COL1A1 in older patients with CRC. Whether age-related alterations in SP1 activity contribute to this decrease remains unclear and warrants further investigation.
In the overall cohort, a low plasma level of pro-COL1A1 was associated with poorer prognosis. This association was consistent across several clinical subgroups, including sex, depth of tumor invasion (T1+T2 vs. T3+T4), tumor location (colon and rectum), TNM stage (I+II and III+IV), tumor differentiation (high+medium andpoor), tumor size (<4 and≥4 cm), and lymph node status (N0andN1+2). Within each subgroup, patients with a low plasma level exhibited significantly poorer survival compared with those with a high level. Comparative analyses of survival curves demonstrated a consistent pattern in which a low plasma pro-COL1A1 level during follow-up was associated with reduced survival.
The ECM undergoes continuous remodeling, and this dynamic process becomes dysregulated in cancer. Such dysregulation may lead to overactivation of cancer-associated fibroblasts, resulting in increased COL1A1 production and progressive tumor fibrosis through excessive collagen deposition, a process known as desmoplasia (5, 9, 19). Desmoplasia has been proposed to influence tumor behavior and has been associated with reduced T-cell infiltration, impaired antitumor immunity, and modulation of cancer invasiveness (5, 19). However, the role of desmoplasia in CRC remains controversial. In our cohort, a lower plasma level of pro-COL1A1 was associated with poorer survival outcomes. One possible explanation is that a reduced plasma level reflects increased retention or deposition of COL1A1 and pro-COL1A1 within colorectal tumor tissue as part of a desmoplastic response. This process may interact with key oncogenic signaling pathways, including phosphatidylinositol-4,5-biphosphate 3-kinase (PI3K), protein kinase B (PKB), WNT and transforming growth factor beta (TGF-β) signaling, thereby influencing tumor progression and patient prognosis (6-8).
Previous studies have demonstrated that COL1A1 expression in CRC tissue is significantly higher in stages I+II disease than in stage III+IV (12), and that expression is increased in T3+T4 tumors compared with T1+T2 tumors (20). In the present study, however, we observed that patients with T3+T4 tumors exhibited poorer survival outcomes when the plasma level of pro-COL1A1 was low. These findings are consistent with our working hypothesis that a reduced plasma level may reflect increased retention or deposition of pro-COL1A1 within CRC tissue, potentially because of desmoplastic stromal reactions. In addition, a lower plasma level was associated with poorer survival in patients with colon cancer. Colon and rectal cancer have been suggested to represent biologically distinct entities with differences in molecular carcinogenesis (21). Tumor size has also been proposed as a prognostic factor in CRC, although its clinical significance remains controversial, with studies reporting both positive and negative associations with survival (22, 23). The mechanisms linking tumor location, tumor size, and plasma pro-COL1A1 level therefore warrant further investigation.
Previous studies have shown that COL1A1 expression in CRC tissue is lower in patients with N0 disease than in those with N1 or N2 disease (7, 20). Consistent with these findings, we found that among patients with N0 disease, a lower plasma pro-COL1A1 level was associated with poorer survival. In contrast, patients with N1+N2 disease exhibited poor survival outcomes regardless of whether the plasma level was high or low.
Study limitations. Analyses performed for smaller subgroups were limited by sample size and should therefore be interpreted with caution. Accordingly, these findings should be considered hypothesis-generating rather than confirmatory. Interindividual variation in COL1A1 expression may exist, and the relatively small sample size may have limited statistical power, increasing the risk of false-negative associations. Furthermore, as patients were recruited from a single hospital, the generalizability of the findings is limited and requires validation in independent cohorts. Finally, potential factors influencing carcinogenesis, including environmental and lifestyle exposures, were not assessed, nor were data available on fibrotic activity within the tumor tissue.
Conclusion
These findings suggest that the plasma level of pro-COL1A1 may serve as a prognostic biomarker for long-term survival in patients with CRC. We speculate that fibrotic activity and COL1A1 expression in CRC tissue may be reflected by the level of plasma pro-COL1A1. Nonetheless, further studies are required to validate these findings, elucidate the underlying regulatory mechanisms, and determine the potential clinical utility of plasma pro-COL1A1 as a prognostic biomarker in CRC.
Conflicts of Interest
The Authors declare no conflicts of interest.
Authors’ Contributions
JD, LS, DW and SDAT designed the research and prepared the main manuscript. KL and ED provided patient blood samples and were responsible for patient data and follow-up. LS and DW prepared clinical samples and performed the laboratory work. JD, LS, DW and SDAT analyzed the data and performed statistical analysis. All Authors reviewed the results and approved the final manuscript.
Funding
This work received grants from Division of Medical Diagnostics, Region Jönköping County, Sweden (FUTURUM-1025484).
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis or presentation of this manuscript.
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