Abnormal vascular network complexity: a new phenotypic marker in hereditary non-polyposis colorectal cancer syndrome

Abstract

Background: Hereditary non-polyposis colorectal cancer (HNPCC) (Lynch cancer family syndrome I (LCFS1) and II (LCFS2)) is one of the most common hereditary cancer disorders. HNPCC results from dominantly inherited germline mutations in mismatch repair (MMR) genes, leading to genomic instability and cancer. No predictive physical signs of HNPCC are available to date. Aims: Increased complexity in tumour associated vascular growth has been reported. Here, we tested the hypothesis that an increased vascular network complexity is a phenotypic marker for LCFS2. Methods: Fourteen subjects from an LCFS2 kindred (gene carriers, n = 5; non-carriers, n = 9) and 30 controls were examined. Fractal dimension (D) at two scales (D (1-46), and D (1-15), tortuosity (minimum path dimension, Dmin), and relative Lempel-Ziev complexity (L-Z) of the vascular networks from the lower gingival and vestibular oral mucosa were measured. Results: LCFS2 networks exhibited a significantly increased overall complexity at both larger (D (1-46) In the present study, we tested the hypothesis that an increased vascular network complexity is a phenotypic marker for LCFS2. METHODS SubjectsFourteen surviving members from a large Southern Italy LCFS2 kindred (eight males, six females; aged 40.2 (11.7) years (range 26-71)) were examined. Detailed characteristic features of this extensively affected family have been reported previously, including early age of onset of tumours, full details of the pedigree, clinical parameters, increased frequency of CRCs (mainly with proximal location), as well as high occurrence of gastric, endometrial, and multiple primary malignancies.12-14 LCFS2 gene mutation carriers (n = 5) were differentiated from non-carriers (n = 9) using a previously established linkage analysis.15 16 Two of five gene carrier patients had a history of proven cancer at the time of examination. Given the specific end point of the present study, family members without genetic testing available were excluded (four males, one female; aged 16.2 (5.7) years (range 10-18)). Thirty genetically unrelated age and sex matched healthy controls (17 males, 13 females; aged 40.0 (10.5) years (range 26-71)) were also enrolled. None of the examined subjects had known inherited connective tissue or vascular diseases. No cases of CRC were present in the family history or pedigrees of controls. Approval by the research ethics committee and informed consent for examination and photographic documentation were obtained. Oral vascular network analysisThe lower gingival and vestibular oral mucosa was chosen as the study area due to its high vasculature pattern visibility and easy accessibility. A 704 mm 2 size (32622 mm) area of the lower gingival and vestibular oral mucosa was photographed for each subject (1:1 ratio, orthogonal projection). All photographs were taken by a single operator using a Yashica Dental Eye photocamera with an automated on-axis flashbulb and a 55 mm f 1:4 Yashica lens (Yashica-Kyocera Co., Kyoto, Japan). Kodak Elite Chrome 100 ISO/21 DIN fil...

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

“…Patterns of nonlinear scaling rules define fractals, which can be measured in terms of complexity and homogeneity. Fractal geometry has been used to quantitate biological processes, such as tumor boundaries, vascular architecture, angiogenesis (8,10,23,24), bone tissue organization during regeneration (39), and liver fibrosis in rats and humans (5,12,25). Fractal analysis of collagen images provided quantitative measurements for the morphological observations.…”

Oral Mucosal Microvascular Abnormalities: An Early Marker of Bronchopulmonary Dysplasia

“…We have found that these abnormalities are not limited to the lung, but the BPD-associated oral microvessel networks exhibit a significantly increased overall complexity at both larger and smaller scales, together with an increased destructured randomness. The D results for the vascular networks of the BPD infants display intermediate characteristics between the diffusionlimited aggregation behavior of control networks and the percolation-like scaling of tumor-associated vascular networks (19). In contrast, vessel tortuosity was comparable between the groups.…”

“…To deliver oxygen and nutrients to all of the cells of the body, blood vessels must have fractal properties (33), and their branching pattern is very similar to the growth model called diffusion-limited aggregation. Furthermore, it has previously been shown that fractal dimension (D) and other fractal characteristics can be used to identify abnormal vascular patterns, including corneal (34), retinal (35), and tumor-associated neovascular growth (19,36). The precise mechanisms underlying the observed increased vascular complexity remain unclear, although extracellular matrix is known to play an important role in angiogenesis and blood vessel geometry (37,38), and changes in extracellular matrix components have been previously reported in experimental models and patients with BPD (39,40).…”

Congenital Oral Mucosal Abnormalities in True Umbilical Cord Knots

“…In order to deliver oxygen and nutrients to all the cells of the body, blood vessels must have fractal properties [29], and their branching pattern is very similar to the growth model called diffusion-limited aggregation. Fractal dimension (D) and other fractal characteristics can be used to identify abnormal vascular patterns, including corneal [30], retinal [31], and tumor-associated neovascular growth [20,32,33]. We speculate that the observed increased complexity and destructured randomness of the oral vascular networks in newborns with true umbilical cord knots may be the result of a possible abnormality in the ECM microarchitecture.…”

“…Vascular network analysis was essentially performed as described [20]. High-resolution photographs of the area of interest were obtained for each subject (size: 704 mm 2 , 1:1 ratio, orthogonal projection).…”