Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment. This is largely due to PDAC being associated with a dense and active stroma and tumor fibrosis (desmoplasia). Desmoplasia is characterized by excessive degradation and formation of the extracellular …
Journal:
Authors:
- Willumsen N,
- Ali SM,
- Leitzel K,
- Drabick JJ,
- Yee N,
- Polimera HV,
- Nagabhairu V,
- Krecko L,
- Ali A,
- Maddukuri A,
- Moku P,
- Poullose J,
- Menon H,
- Pancholy N,
- Costa L,
- Karsdal MA,
- Lipton A,
Post-translational modifications of vimentin reflect different pathological processes associated with non-small cell lung cancer and chronic obstructive pulmonary disease.
Vimentin has shown to be highly implicated in cancer initiation and progression. Vimentin is often a target of post-translational modifications (PTMs) which can be disease specific, thus targeting these specific modifications can be of high biomarker potential. In this study we set out to evaluate t…
Journal:
Authors:
- Nissen N,
- Karsdal MA,
- Willumsen N,
Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer.
Hyaluronan (HA) and collagen are highly expressed in pancreatic cancer (PC) stroma. HA and collagen accumulation increase tumor interstitial fluid pressure, compromising blood flow and drug penetration. The aim of this biomarker study was to determine the clinical utility of serum HA and the propept…
Journal:
Authors:
- Chem IM,
- Willumsen N,
- Dehlendorff C,
- Johansen AZ,
- Jensen BV,
- Hansen CP,
- Hasselby JP,
- Bojesen SE,
- Pfeiffer P,
- Nielsen Se,
- Holländer NH,
- Yilmaz Mk,
- Karsdal MA,
- Johansen JS,
Clinical Relevance of Collagen Protein Degradation Markers C3M and C4M in the Serum of Breast Cancer Patients Treated with Neoadjuvant Therapy in the GeparQuinto Trial.
Background: Remodeling of extracellular matrix through collagen degradation is a crucial step in the metastatic cascade. The aim of this study was to evaluate the potential clinical relevance of the serum collagen degradation markers (CDM) C3M and C4M during neoadjuvant chemotherapy for breast cance…
Journal:
Authors:
- Banys-Paluchowski M,
- Loibl S,
- Witzel I,
- Mundhenke C,
- Lederer B,
- Solbach C,
- Karn T,
- Marmé F,
- Nekljudova V,
- Schem C,
- Stickeler E,
- Willumsen N,
- Karsdal MA,
- Untch M,
- Müller V,
Low bone turnover levels predict increased risk of cancer
BACKGROUND:
Several epidemiological studies have shown an association between bone mineral density (BMD) and risk of breast cancer in postmenopausal women, but it remains unknown whether bone turnover is associated with increased risk of cancer. The aim of this study was to investigate if markers o…
Journal:
Authors:
- Bager CL,
- Bay F,
- Christiansen C,
- Karsdal MA,
Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology
The extracellular matrix (ECM) plays an important role in cancer progression. It can be divided into the basement membrane (BM) that supports epithelial/endothelial cell behavior and the interstitial matrix (IM) that supports the underlying stromal compartment. The major components of the ECM are th…
Authors:
- Nissen N,
- Karsdal MA,
- Willumsen N,
Serological Assessment of Activated Fibroblasts by alpha-Smooth Muscle Actin (α-SMA): A Noninvasive Biomarker of Activated Fibroblasts in Lung Disorders
OBJECTIVES:
Remodeling of the extracellular matrix (ECM) is a key event in different lung disorders, such as fibrosis and cancer. The most common cell type in the connective tissue is fibroblasts, which transdifferentiate into myofibroblasts upon activation. All myofibroblasts express α-SMA, which …
Journal:
Authors:
- Holm Nielsen S,
- Willumsen N,
- Leeming DJ,
- Daniels SJ,
- brix s,
- Karsdal MA,
- Genovese F,
- Nielsen MJ,
Vastatin (the NC1 domain of human type VIII collagen a1 chain) is linked to stromal reactivity and elevated in serum from patients with colorectal cancer.
Vastatin, a fragment derived from type VIII collagen, is one of the least studied collagen-derived matrikines. Vastatin can be detected in serum but little is known regarding the relevance of serum vastatin in colorectal cancer (CRC). In this study, serum vastatin was measured (ELISA) in 67 healthy …
Journal:
Authors:
- will,
- Jorgensen LN,
- Karsdal MA,
The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.
Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluatio…
Journal:
Authors:
- Woodcock HV,
- Eley JD,
- Platé M,
- Manthakumar CB,
- Martufi M,
- Peace S,
- Joberty G,
- Poeckel D,
- Good RB,
- Taylor AR,
- Zinn N,
- Redding M,
- Forty EJ,
- Hynds RE,
- Santon C,
- Karsdal MA,
- Maher TM,
- Bergamini G,
- Marshall RP,
- Blanchard AD,
- Mercer PF,
- Chambers RC,
Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients
BACKGROUND:
Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated t…
Journal:
Authors:
- Jensen C,
- Madsen DH,
- Hansen M,
- Schmidt H,
- Svane IM,
- Karsdal MA,
- Willumsen N,
Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients (1)
Background
Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated th…
Journal:
Authors:
- Jensen C,
- Madsen D,
- Hansen M,
- Schmidt H,
- Svane IM,
Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients.
Journal:
Authors:
- jensen C,
- Madsen DH,
- hansen M,
- Schmidt H,
- Svane IM,
- Karsdal MA,
- Willumsen N,
A serological marker of the N-terminal neoepitope generated during LOXL2 maturation is elevated in patients with cancer or idiopathic pulmonary fibrosis
OBJECTIVES:
Lysyl oxidase like 2 (LOXL2) is associated with poor prognosis in idiopathic pulmonary disease (IPF) and cancer. We developed an Enzyme-linked immunosorbent assay (ELISA) targeting the LOXL2 neo-epitope generated through the release of the signal peptide during LOXL2 maturation.
DESI…
Journal:
Authors:
- Leeming DJ,
- Willumsen N,
- Sand JM,
- Holm Nielsen S,
- Dasgupta B,
- Brodmerkel C,
- Bager CL,
- Karsdal MA,
Non-invasive profiling of protease-specific elastin turnover in lung cancer: biomarker potential.
PURPOSE:
Elastin is a signature protein of lungs. Increased elastin turnover driven by altered proteolytic activity is an important part of lung tumorigenesis. Elastin-derived fragments have been shown to be pro-tumorigenic, however, little is known regarding the biomarker potential of such elastin…
Authors:
- Thoracius-Ussing J,
- Kehlet SN,
- Rønnow S,
- Karsdal MA,
- Willumsen N,
A fragment of SPARC reflecting increased collagen affinity shows pathological relevance in lung cancer - implications of a new collagen chaperone function of SPARC
The matricellular protein SPARC (secreted proteome acidic and rich in cysteine) is known to bind collagens and regulate fibrillogenesis. Cleavage of SPARC at a single peptide bond, increases the affinity for collagens up to 20-fold. To investigate if this specific cleavage has pathological relevance…
Journal:
Authors:
- Kehlet SN,
- Manon-Jensen T,
- Sun S,
- Brix S,
- Karsdal MA,
- Leeming DJ,
- Willumsen N,
Serum type XVI collagen is associated with colorectal cancer and ulcerative colitis indicating a pathological role in gastrointestinal disorders
Altered extracellular matrix (ECM) remodeling is an important part of the pathology of gastrointestinal (GI) disorders. In the intestine, type XVI collagen (col-16) plays a role in pathogenesis by affecting ECM architecture and induce cell invasion. Measuring col-16 in serum may therefore have bioma…
Journal:
Authors:
- Jensen C,
- Nielsen SH,
- Mortensen JH,
- Kjeldsen J,
- Klinge LG,
- Harling H,
- Jørgensen LN,
- Karsdal MA,
- Willumsen N,
- Leeming DJ,
High turnover of extracellular matrix reflected by specific protein fragments measured in serum is associated with poor outcomes in two metastatic breast cancer cohorts.
Increased extracellular matrix (ECM) formation and matrix metalloprotease (MMP)-mediated ECM degradation are parts of tumorgenesis and generates collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in serum with outcomes in two i…
Authors:
- Lipton A,
- Leitzel K,
- Polimera HV,
- Ali SM,
- Naggabhairu V,
- Marks E,
- Richardson AE,
- Krecko L,
- Ali A,
- Koestler W,
- Esteva FJ,
- Leeming DJ,
- Karsdal MA,
- Willumsen N,
Tumstatin, a Matrikine Derived from Collagen Type IVα3, is Elevated in Serum from Patients with Non-Small Cell Lung Cancer
OBJECTIVES
Fibrosis and cancer are characterized by extracellular matrix (ECM) remodeling. The basement membrane is mainly composed by collagen type IV and laminin. Tumstatin is a matrix metalloproteinase-9 (MMP-9) generated matrikine of collagen type IV α3 chain. We evaluated the potential of tums…
Journal:
Authors:
- Nielsen SH,
- Willumsen N,
- Brix S,
- Sun S,
- Manon-Jensen T,
- Karsdal MA,
- Genovese F,
Quantification of altered tissue turnover in a liquid biopsy: a proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities
Immuno-therapy has begun to revolutionize cancer treatment. However, despite the significant progress achieved in regard to the duration of clinical benefits, a substantial number of patients do not respond to these therapies. To improve the outcome of patients receiving immuno-therapy, there is a n…
Journal:
Authors:
- Willumsen N,
- Thomsen LB,
- Bager CL,
- Jensen C,
- Karsdal MA,
Cathepsin-S degraded decorin are elevated in fibrotic lung disorders - development and biological validation of a new serum biomarker
BACKGROUND:
Decorin is one of the most abundant proteoglycans of the extracellular matrix and is mainly secreted and deposited in the interstitial matrix by fibroblasts where it plays an important role in collagen turnover and tissue homeostasis. Degradation of decorin might disturb normal tissue h…
Journal:
Authors:
- Karsdal MA,
- Leeming DJ,
- Brix S,
- Curran M,
- Brodmerkel C,
- Dasgupta B,
- Willumsen N,
- Bager CL,
- Kehlet SN,
Unique insight into microenvironmental changes in colorectal cancer: Ex vivo assessment of matrix metalloprotease-mediated molecular changes in human colorectal tumor tissue and corresponding non-neoplastic adjacent tissue
Matrix metalloprotease (MMP)-mediated tissue remodeling is one of the malignant changes driving colorectal cancer. Measurement of altered MMP expression/activity is not sufficient to fully understand the effect of MMP-mediated tissue remodeling. Biomarkers are required that specifically reflect the …
Journal:
Authors:
- Willumsen N,
- Bager CL,
- Bay-Jensen AC,
- Kehlet SN,
- Harling H,
- Leeming DJ,
- Karsdal MA,
- Jorgensen LN,
Nidogen-1 Degraded by Cathepsin S can be Quantified in Serum and is Associated with Non-Small Cell Lung Cancer
Loss of basement membrane (BM) integrity is typically associated with cancer. Nidogen-1 is an essential component of the BM. Nidogen-1 is a substrate for cathepsin-S (CatS) which is released into the tumor microenvironment. Measuring nidogen-1 degraded by CatS may therefore have biomarker potential …
Journal:
Authors:
- Willumsen N,
- Bager CL,
- Leeming DJ,
- Bay-Jensen AC,
- Karsdal MA,
Excessive matrix metalloprotease-mediated degradation of interstitial tissue (type I collagen) independently predicts short-term survival in an observational study of postmenopausal women diagnosed with cancer
Extensive tissue remodeling mediated by matrix metalloproteases (MMPs) is an important part of cancer. The aim of this study was to investigate whether serum biomarkers reflecting MMP-mediated degradation of type I collagen (C1M), type IV collagen (C4M) and citrullinated vimentin (VICM) were predict…
Journal:
Authors:
- Willumsen N,
- Bager CL,
- Kehlet SN,
- Dragsbaek K,
- Neergaard JS,
- Hansen HB,
- Bay-Jensen AC,
- Leeming DJ,
- Lipton A,
- Christiansen C,
- Karsdal MA,
Cohort Profile: The Prospective Epidemiological Risk Factor (PERF) study
The world’s population is ageing. In Europe alone, the elderly population over age 65 will double from 88 to 153 million and the fastest growing segment of the population will be those over 80, tripling in number from 24 to 60 million in 2060. Low birth rates and increasing longevity are the key fac…
Journal:
Authors:
- Neergaard JS,
- Dragsbæk K,
- Kehlet SN,
- Hansen HB,
- Hansen G,
- Byrjalsen I,
- Alexandersen P,
- Lindgren LM,
- Bihlet AR,
- Riis BJ,
- Andersen JR,
- Qvist P,
- Karsdal MA,
- Christiansen C,
Excessive collagen turnover products are released during colorectal cancer progression and elevated in serum from metastatic colorectal cancer patients
During cancer progression, the homeostasis of the extracellular matrix becomes imbalanced with an excessive collagen remodeling by matrix metalloproteinases. As a consequence, small protein fragments of degraded collagens are released into the circulation. We have investigated the potential of prote…
Journal:
Authors:
- Kehlet SN,
- Sanz-Pamplona R,
- Brix S,
- Leeming DJ,
- Karsdal MA,
- Moreno V,
Remodeling of the Tumor Microenvironment Predicts Increased Risk of Cancer in Postmenopausal Women: The Prospective Epidemiologic Risk Factor (PERF I) Study
BACKGROUND:
An altered tumor microenvironment is one of the earliest signs of cancer and an important driver of the disease. We have seen previously that biomarkers reflecting tumor microenvironment modifications, such as matrix metalloproteinase (MMP)-degraded type 1 collagen (C1M), MMP-degraded t…
Journal:
Authors:
- Bager CL,
- Willumsen N,
- Kehlet SN,
- Hansen HB,
- Bay-Jensen AC,
- Leeming DJ,
- Dragsbæk K,
- Neergaard JS,
- Christiansen C,
- Høgdall E,
- Karsdal MA,
Collagen degradation products measured in serum can separate ovarian and breast cancer patients from healthy controls: A preliminary study
BACKGROUND:
During cancer the otherwise tightly controlled homeostasis of the extracellular matrix (ECM) is disturbed. The protein composition changes, the ECM stiffens and increased levels of proteases are secreted. The combination of these processes result in release of specific protein fragments…
Journal:
Authors:
- Bager CL,
- Willumsen N,
- Leeming DJ,
- Smith V,
- Karsdal MA,
- Dornan D,
- Bay-Jensen AC,
Serum biomarkers reflecting specific tumor tissue remodeling processes are valuable diagnostic tools for lung cancer
Extracellular matrix (ECM) proteins, such as collagen type I and elastin, and intermediate filament (IMF) proteins, such as vimentin are modified and dysregulated as part of the malignant changes leading to disruption of tissue homeostasis. Noninvasive biomarkers that reflect such changes may have a…
Journal:
Authors:
- Willumsen N,
- Bager CL,
- Leeming DJ,
- Smith V,
- Christiansen C,
- Karsdal MA,
- Dornan D,
- Bay-Jensen AC,
Mammographic texture resemblance generalizes as an independent risk factor for breast cancer
Breast density has been established as a major risk factor for breast cancer. We have previously demonstrated that mammographic texture resemblance (MTR), recognizing the local texture patterns of the mammogram, is also a risk factor for breast cancer, independent of percent breast density. We exami…
Journal:
Authors:
- Nielsen M,
- Vachon CM,
- Scott CG,
- Chernoff K,
- Karemore G,
- Karssemeijer N,
- Lillholm M,
- Karsdal MA,
Extracellular matrix specific protein fingerprints measured in serum can separate pancreatic cancer patients from healthy controls
BACKGROUND:
Pancreatic cancer (PC) is an aggressive disease with an urgent need for biomarkers. Hallmarks of PC include increased collagen deposition (desmoplasia) and increased matrix metalloproteinase (MMP) activity. The aim of this study was to investigate whether protein fingerprints of specifi…
Journal:
Authors:
- Willumsen N,
- Bager CL,
- Leeming DJ,
- Smith V,
- Karsdal MA,
- Dornan D,
- Bay-Jensen AC,
A novel and automatic mammographic texture resemblance marker is an independent risk factor for breast cancer
OBJECTIVE:
We investigated whether breast cancer is predicted by a breast cancer risk mammographic texture resemblance (MTR) marker.
METHODS:
A previously published case-control study included 495 women of which 245 were diagnosed with breast cancer. In baseline mammograms, 2-4 years prior to d…
Journal:
Authors:
- Nielsen M,
- Karemore G,
- Loog M,
- Raundahl J,
- Karssemeijer N,
- Otten JD,
- Karsdal MA,
- Vachon CM,
- Christiansen C,
Serum N-Terminal Propeptide of Collagen Type I is Associated with the Number of Bone Metastases in Breast and Prostate Cancer and Correlates to Other Bone Related Markers
BACKGROUND:
A number of biomarkers have been proven potentially useful for their ability to indicate bone metastases (BM) in cancer patients. The aim of this study was to investigate the relative utility of a newly developed N-terminal propeptide of collagen type I (PINP) human serum assay for the …
Journal:
Authors:
- Leeming DJ,
- Koizumi M,
- Qvist P,
- Barkholt V,
- Zhang C,
- Henriksen K,
- Byrjalsen I,
- Karsdal MA,
Low-dose transdermal estradiol induces breast density and heterogeneity changes comparable to those of raloxifene
The aim of this study was to investigate whether transdermal low-dose estradiol treatment induces changes in mammographic density or heterogeneity compared with raloxifene, whether if these changes relate to changes in bone formation/resorption markers, and whether these findings indicate elevation …
Journal:
Authors:
- Nielsen M,
- Raundahl J,
- Pettersen PC,
- Loog M,
- Karemore G,
- Karsdal MA,
- Christiansen C,
Does increased local bone resorption secondary to breast and prostate cancer result in increased cartilage degradation?
BACKGROUND:
Breast and prostate cancer patients often develop lesions of locally high bone turnover, when the primary tumor metastasizes to the bone causing an abnormal high bone resorption at this site. The objective of the present study was to determine whether local increased bone turnover in br…
Journal:
Authors:
- Leeming DJ,
- Byrjalsen I,
- Qvist P,
- Koizumi M,
- Lynnerup N,
- Fregerslev M,
- Sørensen MG,
- Christiansen C,
- Karsdal MA,
Biochemical approach to the detection and monitoring of metastatic bone disease: What do we know and what questions need answers?
Metastatic spread to bones frequently occurs in several types of cancer diseases, in particular breast, prostate, and lung cancer. Infiltration of bone by tumour cells is a source of several complications including severe bone pain, spinal cord compression, hypercalcemia, pathologic fractures, all r…
Journal:
Authors:
- Tankó LB,
- Karsdal MA,
- Christiansen C,
- Leeming DJ,
Alpha CTX as a biomarker of skeletal invasion of breast cancer: immunolocalization and the load dependency of urinary excretion
We recently showed that increased urinary excretion of the cross-linked, nonisomerized form of the C-telopeptide of collagen type I (alphaalphaCTX) could be a sensitive indicator of the presence of bone metastases in breast cancer patients. The present study was sought to investigate (a) the localiz…
Journal:
Authors:
- Leeming DJ,
- Delling G,
- Koizumi M,
- Henriksen K,
- Karsdal MA,
- Li B,
- Qvist P,
- Tankó LB,
- Byrjalsen I,