Travelling-wave analysis of a model of tumour invasion with degenerate, cross-dependent diffusion

In this paper, we carry out a travelling-wave analysis of a model of tumour invasion with degenerate, cross-dependent diffusion. We consider two types of invasive fronts of tumour tissue into extracellular matrix (ECM), which represents healthy tissue. These types differ according to whether the density of ECM far ahead of the wave front is maximal or not. In the former case, we use a shooting argument to prove that there exists a unique travelling-wave solution for any positive propagation speed. In the latter case, we further develop this argument to prove that there exists a unique travelling-wave solution for any propagation speed greater than or equal to a strictly positive minimal wave speed. Using a combination of analytical and numerical results, we conjecture that the minimal wave speed depends monotonically on the degradation rate of ECM by tumour cells and the ECM density far ahead of the front.

Intraepithelial growth pattern for eyelid sebaceous carcinoma: a cohort of 214 patients from a single institution

AimsTo determine the distribution of three different intraepithelial growth patterns (pagetoid, bowenoid and papillary) in eyelid sebaceous carcinoma (SC) and correlate them with the clinical characteristics and prognosis.MethodsA retrospective cohort study. The medical charts and pathological sections were retrospectively reviewed. All eligible patients were followed up for recurrence, metastasis and tumour-related mortality. The clinical significance of each intraepithelial growth pattern was determined by Cox regression.ResultsOf the 214 patients, 67 (31%) presented with intraepithelial invasion, among them, 34 (16%) were pagetoid, 27 (13%) were bowenoid and 6 (2.8%) were papillary. Patients of pagetoid intraepithelial spread showed significantly longer diagnostic delay (p=0.001) and more initial misdiagnoses of blepharitis (p=0.035). After a median follow-up period of 34.0 months, 67 (46%) patients in the non-intraepithelial group, 17 (50%) in the pagetoid group, 8 (30%) in the bowenoid group and 2 (33%) in the papillary group recurred. And 30 (20%) patients in the non-intraepithelial group, 9 (27%) in the pagetoid group and 4 (15%) in the bowenoid group developed metastasis. Moreover, 15 (10%) patients in the non-intraepithelial group, 6 (18%) in the pagetoid group and 1 (3.7%) in the bowenoid group died of SC. Cox regression indicated that pagetoid intraepithelial growth pattern was remarkably associated with increased chances of tumour-related mortality (HR=2.95, 95% CI 1.14 to 7.64, p=0.026).ConclusionsIntraepithelial tumour invasion was presented in nearly one third of patients with eyelid SC. Pagetoid intraepithelial neoplasia, the predominant growth pattern, significantly increased the risk of tumour-related mortality. Meticulous histopathological intraepithelial examination is recommended for every patient of eyelid SC. Special attention should be paid to those with pagetoid invasion, who may require more intensive managements.

Negative regulation of TGFβ-induced apoptosis by RAC1B enhances intestinal tumourigenesis

RAC1B is a tumour-related alternative splice isoform of the small GTPase RAC1, found overexpressed in a large number of tumour types. Building evidence suggests it promotes tumour progression but compelling in vivo evidence, demonstrating a role in driving tumour invasion, is currently lacking. In the present study, we have overexpressed RAC1B in a colorectal cancer mouse model with potential invasive properties. Interestingly, RAC1B overexpression did not trigger tumour invasion, rather it led to an acceleration of tumour initiation and reduced mouse survival. By modelling early stages of adenoma initiation we observed a reduced apoptotic rate in RAC1B overexpressing tumours, suggesting protection from apoptosis as a mediator of this phenotype. RAC1B overexpressing tumours displayed attenuated TGFβ signalling and functional analysis in ex vivo organoid cultures demonstrated that RAC1B negatively modulates TGFβ signalling and confers resistance to TGFβ-driven cell death. This work defines a novel mechanism by which early adenoma cells can overcome the cytostatic and cytotoxic effects of TGFβ signalling and characterises a new oncogenic function of RAC1B in vivo.

Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer

Background: cervical cancer is one of the most common malignancies in women worldwide and its management remains challenging and complex. As Cytochrome4Z1 (CYP4Z1) is overexpressed in many tumours, its expression in cervical cancer is unknown. Therefore, the present study aimed to evaluate CYP4Z1 expression in cervical cancers. Methods: CYP4Z1 expression was immunohistochemically assessed in 100 cases of cervical cancers along with ten normal cervix tissues, and the enzyme’s relationship to several clinicopathological features and survival was explored. Results: CYP4Z1 was strongly expressed in 55% of cervical cancer patients. Normal cervix samples were negative for CYP4Z1 expression. Importantly, this expression was significantly found in patients with the late stage of the disease, lymph node metastasis, and high tumour invasion (p < 0.05). Interestingly, CYP4Z1 expression was significantly correlated with shorter survival times of cervical cancer patients. Univariate analysis showed that CYP4Z1 expression, tumour stage, lymph node metastasis, and tumour invasion were significantly correlated with patient survival (p < 0.05). The multivariate analysis revealed that only CYP4Z1 expression and tumour stage were significantly correlated with patient survival (p < 0.05). Conclusions: CYP4Z1 expression is associated with cervical cancer patients’ survival and may serve as an independent predictor of poor prognosis in cervical cancer patients.

Deletion of Col15a1 Modulates the Tumour Extracellular Matrix and Leads to Increased Tumour Growth in the MMTV-PyMT Mouse Mammary Carcinoma Model

Basement membrane (BM) zone-associated collagen XV (ColXV) has been shown to suppress the malignancy of tumour cells, and its restin domain can inhibit angiogenesis. In human breast cancer, as well as in many other human carcinomas, ColXV is lost from the epithelial BM zone prior to tumour invasion. Here, we addressed the roles of ColXV in breast carcinogenesis using the transgenic MMTV-PyMT mouse mammary carcinoma model. We show here for the first time that the inactivation of Col15a1 in mice leads to changes in the fibrillar tumour matrix and to increased mammary tumour growth. ColXV is expressed by myoepithelial and endothelial cells in mammary tumours and is lost from the ductal BM along with the loss of the myoepithelial layer during cancer progression while persisting in blood vessels and capillaries, even in invasive tumours. However, despite the absence of anti-angiogenic restin domain, neovascularisation was reduced rather than increased in the ColXV-deficient mammary tumours compared to controls. We also show that, in robust tumour cell transplantation models or in a chemical-induced fibrosarcoma model, the inactivation of Col15a1 does not affect tumour growth or angiogenesis. In conclusion, our results support the proposed tumour suppressor function of ColXV in mammary carcinogenesis and reveal diverse roles of this collagen in different cancer types.

An overview of the α4β1 integrin and the potential therapeutic role of its antagonists

: This article presents a simplified view of integrins with emphasis on the α4 (α4β1/VLA-4) integrin. Integrins are heterodimeric proteins expressed on the cell surface of leukocytes that participate in a wide variety of functions, such as survival, growth, differentiation, migration, inflammatory responses, tumour invasion, among others. When the extracellular matrix is degraded or deformed, cells are forced to undergo responsive changes that influence remodelling during physiological and pathological events. Integrins recognize these changes and trigger a series of cellular responses, forming a physical connection between the interior and the outside of the cell. The communication of integrins through the plasma membrane occurs in both directions, from the extracellular to the intracellular (outside-in) and from the intracellular to the extracellular (inside-out). Integrins are valid targets for antibodies and small molecule antagonists. One example is the monoclonal antibody natalizumab, marketed under the name of TYSABRI®, used in the treatment of recurrent multiple sclerosis, which inhibits the adhesion of α4 integrin to its counter-receptor. α4β1 Integrin antagonists are summarized here and their utility as therapeutics discussed.

Roughness and dynamics of proliferating cell fronts as a probe of cell-cell interactions

Juxtacellular interactions play an essential but still not fully understood role in both normal tissue development and tumour invasion. Using proliferating cell fronts as a model system, we explore the effects of cell-cell interactions on the geometry and dynamics of these one-dimensional biological interfaces. We observe two distinct scaling regimes of the steady state roughness of in-vitro propagating Rat1 fibroblast cell fronts, suggesting different hierarchies of interactions at sub-cell lengthscales and at a lengthscale of 2–10 cells. Pharmacological modulation significantly affects the proliferation speed of the cell fronts, and those modulators that promote cell mobility or division also lead to the most rapid evolution of cell front roughness. By comparing our experimental observations to numerical simulations of elastic cell fronts with purely short-range interactions, we demonstrate that the interactions at few-cell lengthscales play a key role. Our methodology provides a simple framework to measure and characterise the biological effects of such interactions, and could be useful in tumour phenotyping.Proliferating cell fronts underpin wound healing, tumour invasion, and morphogenesis, and are governed by a complex and still not fully understood interplay of multiple mechanical and chemical factors. From a physics perspective, these cell fronts can be described as elastic interfaces in disordered media. Thus, analysing their geometric properties and dynamics can reveal the characteristic lengthscales of the dominant interactions, and point towards the underlying biological pathways. Here, we show that the roughness of proliferating fronts of Rat1 fibroblasts is governed by two different hierarchies of interactions, with distinct behaviour at sub-cell and few-cell lengthscales. Using in-vitro scratch assays, we find moreover that pharmacological modulators significantly affect the proliferation speed of the cell fronts as well as the evolution of their roughness, increased when cell-cell communication via gap junctions is perturbed, and decreased when cell division is repressed. We determine that our experimental observations cannot be reproduced by numerical simulations of elastic cell fronts with purely short-range interactions, demonstrating the key role of juxtacellular interactions at few-cell lengthscales. Our approach provides a simple framework to measure and characterise the biological effects of such interactions, and could be useful in tumour phenotyping.

Clinicopathologic characteristics, survival, and treatments for gastric adenosquamous carcinoma: a population-based study

Background Gastric adenosquamous carcinoma (gasc) is a rare entity with distinctive characteristics that are not fully understood. In the present study, we evaluated the characteristics of this rare disease. Methods The U.S. Surveillance, Epidemiology, and End Results program database was searched to determine the clinicopathologic features, prognostic factors, and treatments for 246 patients with gasc and 42,735 patients with gastric adenocarcinoma (gac). Results Relative to gac, gasc is associated with higher proportions of cardia involvement, high-grade tumours, deep tumour invasion, metastatic lymph nodes, and chemotherapy treatment. In patients who underwent potentially curative surgery (pcs), gasc was associated with a higher proportion of radiotherapy use and poorer overall survival (p < 0.001), although no significant difference (p = 0.802) was observed after propensity score matching (psm). Multi­variate analysis after psm revealed that the independent prognostic factors for gasc were TNM stage [hazard ratio (hr): 1.512; p = 0.021] and regional nodes examined (hr: 0.588; p = 0.02). In patients with advanced disease, no significant difference in survival between gasc and gac was observed (p = 0.212), although survival was significantly poorer for gasc after psm (p = 0.019). Multivariate analysis after psm revealed that the independent prognostic factors for gasc were invasion depth (hr: 1.303; p = 0.036) and chemotherapy (hr: 0.444; p < 0.001). Conclusions Relative to gac, gasc was associated with more aggressive features, although survival outcomes were similar after pcs. Chemotherapy remains a mainstay of treatment for patients with advanced gasc, but its role remains unclear for patients who are undergoing pcs.

Retrobulbar chlorpromazine injection in a child with gliosarcoma invasion into the orbits

This paper has two main purposes: (1) to report a rare case of paediatric gliosarcoma that invaded the surrounding orbit and (2) to demonstrate chlorpromazine injection as a potential treatment option for blind, painful eye caused by tumour invasion. A 12-year-old man who presented with headaches was found to have glioblastoma multiforme and it was excised and treated with radiation and chemotherapy. Seven months later, the tumour recurred as gliosarcoma, a rare variant of glioblastoma multiforme containing distinct gliomatous and sarcomatous components. In spite of treatment, the tumour progressed and eventually invaded into the right orbit. He subsequently developed a proptotic, blind, painful eye and was treated with retrobulbar chlorpromazine injection, which provided immediate symptomatic relief.