Colorectal cancer (CRC) diagnosis and prognostic stratification are based on histopathologic assessment of cell or nuclear pleomorphism, aberrant mitotic figures, altered glandular architecture, and ...other phenomic abnormalities. This complexity is driven by oncogenic perturbation of tightly coordinated spatiotemporal signaling to disrupt multiple scales of tissue organization. This review clarifies molecular and cellular mechanisms underlying common CRC histologic features and helps understand how the CRC genome controls core aspects of tumor aggressiveness. It further explores a spatiotemporal framework for CRC phenomics based on regulation of living cells in fundamental and organotypic model systems. The review also discusses tissue homeostasis, considers distinct classes of oncogenic perturbations, and evolution of cellular or multicellular cancer phenotypes. It further explores the molecular controls of cribriform, micropapillary, and high-grade CRC morphology in organotypic culture models and assesses relevant translational studies. In addition, the review delves into complexities of morphologic plasticity whereby a single molecular signature generates heterogeneous cancer phenotypes, and, conversely, morphologically homogeneous tumors show substantive molecular diversity. Principles outlined may aid mechanistic interpretation of omics data in a setting of cancer pathology, provide insight into CRC consensus molecular subtypes, and better define principles for CRC prognostic stratification.
Compelling observational and laboratory evidence supports vitamin D3 as a chemopreventive agent against colorectal cancer (CRC), yet its efficacy as such has not been demonstrated in clinical ...studies. Low-dose vitamin D3 intervention in unselected study populations, combined with a paucity of surrogate endpoint biomarkers to facilitate early phase clinical studies, may have hindered clinical translation of the cancer-suppressive effects of vitamin D3. This study aims to address these shortcomings and optimise a phase II biomarker-driven clinical study that may finally establish the efficacy of vitamin D3 in CRC chemoprevention. Using three-dimensional (3D) organotypic culture models of CRC gland architecture, vitamin D3 has been shown to exert pro-morphogenic effects and promote the maintenance of organised, epithelial gland morphology; providing a novel rationale by which this secosteroid suppresses malignant progression and invasion. This study further explores the molecular framework of vitamin D3 morphology control using the same 3D model system alongside translational studies in human CRC tissue, to identify mechanistic biomarkers of vitamin D3 cancer control that may facilitate future clinical studies. A safe, yet cancer-suppressive dose of vitamin D3 remains to be defined. It is hoped that future work evaluating the effects of an adequate, cancer-suppressive dose of vitamin D3 on novel endpoint biomarkers defined in this study may finally define the chemopreventive value of vitamin D3.
The management of small abdominal aortic aneurysms (AAA) is by ultrasound surveillance. The study aimed to calculate their growth rate, identify risk factors and determine appropriate screening ...intervals. The local screening programme and hospital records were used to identify patients with a small (< 5.5 cm) AAA. The dates and maximum diameter of serial scans of patients with two or more scans were obtained. Patients were subdivided by 0.5 cm increments above 3.0 cm. The rate of growth was calculated by linear regression for each patient using both the absolute measurements and logarithmically (ln) transformed measurements. The 95th centile of growth rate within each subgroup was used to estimate the minimum time to grow to 5.5 cm. A total of 252 were included. The mean (± SD) AAA size on the initial scan was 3.9 (± 0.7) cm. Statin use and initial size were predictive factors for the growth rate. The median rate of growth increased according to size from 0.075 to 0.432 cm/year for AAA < 3.5 cm and > 5.0 cm, respectively. It also steadily increased for ln measurements from 0.022 (or 2.2%/year) to 0.078 or (7.8%/year). The minimum time (months) to reach 5.5 cm was 61, 17, 11 and 5 for AAA < 3.5 cm, 3.5–3.9 cm, 4.0–4.4 cm and 4.5–4.9 cm, respectively. Based on ln measurements, the times were similar at 60, 17, 10 and 4 months. In conclusion, the rate of growth increased steadily with AAA size. An aneurysm < 3.5 cm does not require a repeat scan for 5 years, while those measuring 3.5–3.9 cm and 4.0–4.4 cm require a repeat scan after 17 and 11 months.
Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in ...three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)2D3,theactive form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted "Swiss cheese-like" cribriform morphology (CM) comprising multiple abnormal "back to back" lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors.
INTRODUCTION
The National Health Service (NHS) Cancer Plan guidelines recommend a maximum 2-week wait from referral to first appointment, and 2 months from referral to treatment for primary cancers. ...However, there are currently no guidelines available for metastatic disease. In the UK, nearly half of all colorectal cancer patients develop hepatic metastases. Timely, surgical resection offers the potential for cure. The aim of this study was to audit current practice for colorectal liver metastases in a regional hepatobiliary unit, and compare this to the NHS Cancer Plan standards for primary disease.
PATIENTS AND METHODS
A retrospective review of the unit's database was performed for all hepatic metastases referrals from January 2006 to December 2008. The dates of referral, first appointment, investigations and initiation of treatment, along with patient's age and sex, were recorded on Microsoft Excel and analysed. Time was expressed as mean ± SD in days.
RESULTS
A total of 102 patients with hepatic metastases were identified. Five were excluded due to incomplete data. The average time from referral to first appointment was 10.6 ± 9.4 days and the average time from referral to treatment was 38.5 ± 28.6 days. Seventy-five (72.7%) had surgical intervention, of whom 37 also had chemotherapy.
CONCLUSIONS
The data compare favourably to the NHS Cancer Plan guidelines for primary malignancy, demonstrating that a regional hepatobiliary unit is capable of delivering a service for colorectal liver metastases that adheres to the NHS Cancer Plan. Therefore, the NHS Cancer Plan can be applied to this cohort.
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