Breast Cancer: Modelling and Detection

This paper reviews a number of the mathematical models used in cancer modelling and then chooses a specific cancer, breast carcinoma, to illustrate how the modelling can be used in aiding detection. We then discuss mathematical models that underpin mammographic image analysis, which complements models of tumour growth and facilitates diagnosis and treatment of cancer. Mammographic images are notoriously difficult to interpret, and we give an overview of the primary image enhancement technologies that have been introduced, before focusing on a more detailed description of some of our own recent work on the use of physics-based modelling in mammography. This theoretical approach to image analysis yields a wealth of information that could be incorporated into the mathematical models, and we conclude by describing how current mathematical models might be enhanced by use of this information, and how these models in turn will help to meet some of the major challenges in cancer detection

A shape-space-based approach to tracking myocardial borders and quantifying regional left-ventricular function applied in echocardiography.

This paper presents a new semi-automatic method for quantifying regional heart function from two-dimensional echocardiography. In the approach, we first track the endocardial and epicardial boundaries using a new variant of the dynamic snake approach. The tracked borders are then decomposed into clinically meaningful regional parameters, using a novel interpretational shape-space motivated by the 16-segment model used in clinical practice for qualitative assessment of heart function. We show how a quantitative and automatic scoring scheme for the endocardial excursion and myocardial thickening can be derived from this. Results illustrating our approach on apical long-axis two-chamber-view data from a patient with a myocardial infarct in the apical anterior/inferior region of the heart are presented. In a case study (five patients, nine data sets) the performance of the tracking and interpretation techniques are compared with manual delineations of borders using a number of quantitative measures of regional comparison

A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione-conjugated MQ (GS-MQ). Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy

Tight junction protein claudin-2 promotes self-renewal of human colorectal cancer stem-like cells

Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence free survival following 5-fluorouracil–based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDH High CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDH High phenotype. Next-generation sequencing in ALDH High cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer. Significance: Claudin-2-mediated regulation of YAP activity and miR-222-3p expression drives CSC renewal in colorectal cancer, making it a potential target for therapy.Sophie Paquet-Fifield ... Melissa J. Davis ... et. a