Author: Claire Hornung

The Minor Collagen Hypothesis

Collagen is a crucial protein that provides structural support and strength to tissues throughout the body. However, there is a group of highly specialized minor collagens that may play a critical role in cancer progression. Most research on the biology of collagens has focused on the abundant collagens, but the highly specialized minor collagens that are expressed only at certain developmental stages may be deregulated in cancer.

The Hypothesis

Minor collagens are widely expressed during embryogenesis, as they organize the extracellular matrix (ECM) to support tissue development. However, in adult tissues, minor collagens become restricted to a few specific organs and are expressed at very low levels.

Recent studies have suggested that minor collagens may become deregulated in cancer, where they are highly upregulated in tumor tissues. This upregulation is thought to occur as the ECM is reorganized during tumor development and progression. We have chosen to call this hypothesis “The Minor Collagen Hypothesis”. We hypothesize that minor collages, which are normally restricted to embryonic tissues, may become active again in adult tissues as cancer progresses. The Minor Collagen Hypothesis proposes that this reactivation may be a key component in in tumor growth and invasion by altering the composition of the ECM.

Applying The Minor Collagen Hypothesis in clinical research

Biomarkers are important for indicating the presence or severity of a disease, and in cancer, they are crucial for early detection, monitoring of cancer progression, and guiding treatment decisions.

In general, several collagen biomarkers are overexpressed in cancer. However, minor collagens may offer a more specific biomarker for certain types of cancer. For example, recent research has shown that certain subtypes of cancer-associated fibroblasts (CAFs) express specific minor collagens. These collagens can be detected in blood, making them potential targets for drug development aimed at CAFs.

This hypothesis offers researchers new possibilities and highlights the need for more specific biomarkers for cancer diagnosis and treatment that could lead to better patient outcomes. Identifying biomarkers that detect specific minor collagens could be a breakthrough in cancer research and might shed light on an overlooked aspect of cancer progression.

Minor collagens are typically expressed during embryogenesis or tissue development and are expressed at low levels afterward. In cancer, however, these specialized collagens are expressed again to form an environment conducive to cancer growth. The abundant major collagens are also expressed during tissue development and growth spurts in childhood and adolescence but tapers off in adulthood. The relative induction as a function of cancer is greater for the minor collagens compared to the major collagens. This could mean better biomarker performance. 

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Understanding Fibrosis Remodeling in Animal Models

Animal testing is a crucial aspect of drug development, mandated by the FDA for all premature drugs in development. However, a critical question arises: how can we be sure that the pathology observed in rodents is reflective of the same pathology in humans? This is a significant concern for the medical community because of the potential for negative consequences if clinical trials are based on inaccurate preclinical data as we see in humans. Why then is it so important to measure biomarker formations in rodents? Because it matters whether it mimics the right pathology.

The process of transitioning from preclinical to clinical trials is critical to success. Histological stages are built on human tissue sections and used for comparison to create an appropriate animal model. However, none of the existing rodent models currently develop nonalcoholic steatohepatitis (NASH) as seen in humans. This discrepancy raises concerns regarding the usefulness of rodent models for preclinical studies.

Despite these concerns, it is still essential to measure biomarker formations in rodents. The reason being, it matters whether the biomarker mimics the correct pathology. Nordic Bioscience has demonstrated increasing formation of both type III collagen (interstitial matrix) and type IV collagen (basement membrane) with continued injury in a rat bile duct ligation model. Collagen III has been shown to be upregulated in human liver fibrosis, including NASH, and is associated with increased severity. On the other hand, collagen IV is a measure of early fibrosis remodeling.

It is critical to understand fibrosis remodeling during disease progression in both animals and humans. With Nordic Bioscience’s biomarkers, researchers can improve translation between the preclinical and clinical practice. The use of biomarkers enables researchers to track disease progression and evaluate the effectiveness of potential treatments accurately. Moreover, they can also help identify patients who are likely to respond positively to a particular therapy.

Animal testing remains a critical aspect of drug development, it is essential to understand rodent model limitations. Biomarkers offer an effective way to track the progression of disease accurately. We can identify patients likely to benefit from a specific treatment and improve the transition from preclinical to clinical trials. By leveraging biomarkers in both animal and human models, we can make sure that the right therapy is provided to the right patient—at the right time.

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Are fibroblasts good or are they bad?

We need to talk about the good and the bad fibroblasts – the dangerous fibroblasts that overgrow organs and destroy organ function, but also the necessary specialized fibroblasts in bone, the osteoblasts. 

Fibroblasts are an important type of cell in the human body that play a crucial role in tissue repair and maintenance. However, not all fibroblasts are created equal – there are both good and bad fibroblasts that have vastly different effects on the body.

The dangerous fibroblasts, known as myofibroblasts, are responsible for pathological tissue remodeling in various diseases, such as fibrosis. These fibroblasts overgrow organs and destroy organ function. While myofibroblasts play a role in wound healing, their persistence and unchecked growth can lead to excessive scarring and tissue damage.

On the other hand, there are specialized fibroblasts, such as osteoblasts, that are necessary for maintaining bone health. Osteoblasts are responsible for producing the extracellular matrix that makes up bone tissue, and are crucial in the process of bone formation.

Unfortunately, the success in biomedical sciences such as genomics and proteomics is not paralleled in the medical product development methods, resulting in a lack of translation into improved drug safety and efficacy. This can lead to some antifibrotic treatments having deleterious effects on bone fibroblasts, such as osteoblasts, and may cause unwanted side effects.

In rheumatic diseases, bone inflammation and remodeling phenotypes are proposed to be a result of endochondral bone formation. Studies have identified bone as a possible endocrine organ, and the availability of valid biochemical bone markers suggests that assessing bone turnover should also play an important role in general safety pharmacology.

To address this issue, there is a need for improved methods to assess the effects of treatments on different types of fibroblasts. This is where bone inflammation panels come in – these panels can be used to assess whether a treatment is having a deleterious effect on bone fibroblasts, such as osteoblasts.

In conclusion, while fibroblasts play a crucial role in tissue repair and maintenance, it is important to distinguish between the good and bad fibroblasts. Unchecked growth of myofibroblasts can lead to tissue damage and organ dysfunction, while osteoblasts are necessary for maintaining bone health. Improved methods of assessing the effects of treatments on different types of fibroblasts, such as bone inflammation panels, can help ensure that treatments are safe and effective.

With our bone inflammation panel, you can assess whether your treatment is having a deleterious effect.

Related publications:

Should biochemical markers of bone turnover be considered standard practice for safety pharmacology?

Biochemical markers in osteoarthritis with lessons learned from osteoporosis

Role of biochemical markers in the management of osteoporosis

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The affect on the collagen microenvironment in breast cancer patients

In a recently published study based on a collaboration between Nordic Bioscience, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and Nancy E. and Peter C. Meinig School of Biomedical Engineering, we have examined the effect of copper depletion therapy on the collagen microenvironment in breast cancer patients with a high risk of relapse.

Tetrathiomolybdate (TM) is a novel, copper-depleting compound associated with promising survival in a phase II study of patients with high-risk and triple-negative breast cancer. In the study, levels of all collagen biomarkers were higher in those with the disease, metastatic and adjuvant, as compared with healthy controls. 

We propose a novel mechanism for preventing metastases through altered collagen processing in the tumor microenvironment. We hypothesize that decreased collagen cross-linking and increased degradation caused by the treatment may alter the immune response in the pre-metastatic sites and thereby decrease the metastatic potential.

Preclinical studies revealed decreased collagen deposition, lower levels of myeloid-derived suppressor cells, and higher CD4+ T-cell infiltration in TM-treated mice compared with controls.

In conclusion, the study showed novel mechanisms of TM targeting the TME and immune response with potential applications across cancer types.

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The future of the kidney with a simple urine test

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition that causes the development of cysts in the kidneys. This condition affects millions of people worldwide and can lead to kidney failure if left untreated. One of the biggest challenges in treating ADPKD is identifying biomarkers that can predict disease progression and response to treatment.

Our Renal and Cardiovascular Research team showed that biomarkers of collagen remodeling measured in urine and circulation at baseline are associated with the rate of decline in kidney function in patients with ADPKD. In the study (DIPAK-1), we measured the effect of lanreotide on patients with stage 3 chronic kidney disease. The following demographics were involved:

To assess the effect of lanreotide, the team selected a number of biomarkers that were best suited to assess the effect of the drug on interstitial matrix turnover and basement membrane turnover. We have selected a number of biomarkers:

• PRO-C3, measuring collagen type III formation in serum and urine (interstitial matrix turnover)
• C3M, measuring collagen type III degradation in serum and urine (interstitial matrix turnover)
• PRO-C6, measuring collagen type VI formation in serum and urine. Also measures the release of the bioactive fragment endotrophin, associated with pro-fibrotic and pro-inflammatory processes (interstitial matrix turnover)
• LG1M, measuring Laminin gamma 1 degradation in serum and urine (basement membrane turnover)

The data we found implies that fibrogenesis may be an important pathophysiological process driving ADPKD disease progression. In addition, the use and development of drugs that interfere with fibrogenesis may be promising to halt disease progression in ADPKD. However, we still need to validate in an independent cohort, preferably in early-stage disease.

The findings of the study are significant because they offer new insights into the potential for biomarkers to predict disease progression in ADPKD. This information may help clinicians to identify patients who are at risk of developing kidney failure and to develop more effective treatments to slow or halt disease progression.

We have shown that biomarkers of collagen remodeling are associated with the rate of decline in kidney function in patients with ADPKD. These findings suggest that fibrogenesis may be an important pathophysiological process driving ADPKD disease progression and that the use of drugs that interfere with fibrogenesis may be promising to halt disease progression. Further research is needed to validate these findings in an independent cohort, but the results of this study offer new hope for patients with ADPKD.

We believe it is time to put kidney fibrosis more in the center – even in diseases where other aspects (such as kidney volume) are the focus of attention. At Nordic Bioscience, we have the tools to do so. 

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How much load can the cartilage in the joints absorb?

Mechanical loading is an essential part of the function and maintenance of the joint. Despite the importance of intermittent mechanical loading, this factor is rarely considered in preclinical models of cartilage, limiting their translatability.

The cartilage of the joints of patients with osteoarthritis is negatively affected in their capacity to absorb the load. Despite this pivotal role, mechanical load is rarely a component of translational drug screening assays when testing novel OA treatments.

We showcased our novel translational cartilage loading model in a publication in Applied Sciences.

In a culture plate format well suited for lead candidate screening we investigated the effect of growth factors on ex-vivo cartilage remodeling and the interaction with dynamic intermittent loading. Cartilage remodeling was investigated in the presence of IGF-1 or TGF-β1, as well as a TGF-β receptor 1 (ALK5) kinase inhibitor and assessed with biomarkers for type II collagen formation and fibronectin degradation (FBN-C).

Amongst others, PRO-C2 has shown that not only does mechanical loading preserve cartilage, but it also positively modulates the effect of known growth factors, such as IGF-1.

Screening potential drug candidates in physiological loading conditions could provide a more accurate translation to push forward the urgent medical need for better treatments of osteoarthritis.

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