News Update on Tumour Invasion Research: May – 2019

Molecular Repolarisation of Tumour-Associated Macrophages

The growth microenvironment (TME) consists of animate thing matrix and non-mutated cells supporting tumour growth and development. Tumour-associated macrophages (TAMs) are among the foremost pr immune cells within the TME and are liable for the onset of a smouldering inflammation. TAMs play a crucial  role in oncogenic processes as growth proliferation, growth and metastasis, and that they give a barrier against the cytotoxic effector operate of T lymphocytes and natural killer (NK) cells. However, TAMs are extremely plastic cells which will adopt either pro- or medicinal drug roles in response to environmental cues. Consequently, TAMs represent a sexy target to recalibrate immune responses within the TME. Initial TAM-targeted ways, like scavenger cell depletion or disruption of cap achievement, have shown helpful effects in presymptomatic models and clinical trials. or else, reprogramming TAMs towards a pro-inflammatory and tumouricidal composition has become a sexy strategy in therapy. This work summarises the molecular mechanical device of scavenger cell biology and presents an summary of molecular ways to repolarise TAMs in therapy.[1]

Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signaling

Metastasis is the leading cause of breast cancer–related deaths. Cancer-associated fibroblasts (CAFs), the predominant stromal cell type in the breast tumour microenvironment, may contribute to cancer progression through interaction with tumour cells. Nonetheless, little is known about the details of the underlying mechanism. Here we found that interaction of interleukin 32 (IL32) with integrin β3 (encoded by ITGB3; a member of the integrin family) mediating the cross-talk between CAFs and breast cancer cells plays a crucial role in CAF-induced breast tumour invasiveness. IL32, an ‘RGD’ motif–containing cytokine, was found to be abundantly expressed in CAFs. Integrin β3 turned out to be up-regulated in breast cancer cells during epithelial–mesenchymal transition (EMT). CAF-derived IL32 specifically bound to integrin β3 through the RGD motif, thus activating intracellular downstream p38 MAPK signalling in breast cancer cells. This signalling increased the expression of EMT markers (fibronectin, N-cadherin, and vimentin) and promoted tumour cell invasion. Counteracting IL32 activity, a knockdown of IL32 or integrin β3 led to specific inactivation of p38 MAPK signalling in tumour cells. Blockage of the p38 MAPK pathway also diminished IL32-induced expression of EMT markers and breast cancer cell invasion and metastasis. Thus, our data indicate that CAF-secreted IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling.[2]

Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis

This review aims to provide an overview of recent developments regarding the roles of MMPs in tumour invasion and metastasis. Much of the mortality burden belonging to cancer relates to its ability to invade adjacent tissue and form metastases at distant sites. This would not be possible without remodelling of the ECM, a process which is enabled by the functions of MMPs. Recent studies provide a better understanding of the importance of the biophysical nature of the ECM, how this influences cancer cell motility, and how MMPs act to modify matrix stiffness. The regulation of MMPs and the role of immune cell generated MMPs has also become better understood. All of this provides a framework for the therapeutic targeting of MMPs and recent advances in the development of selective MMPs inhibitors are also reviewed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [3]

EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance

Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies. [4]

Papillary Thyroid Cancer: A Histopathological Review in Accra, Ghana

There is paucity of information on papillary thyroid cancer (PTC) in Ghana. The aim of this study was to determine the relative proportions of thyroid malignancies diagnosed in our institution that were PTC, the trend and the clinico-pathological characteristics.

Materials and Methods: A review of all thyroid malignancies diagnosed in our department from January 1994 to December 2013 was conducted. Data was entered and analysed using SPSS software (Version 23 Chicago).

Results: Papillary thyroid cancer was the commonest thyroid malignancy (52.7%). There was a gradual decline in the numbers of cases during the period under review. Approximately 60.3% of the patients were younger than 40 years. The great majority (77.6%) were females with a female to male ratio of 4:1. Four patients (4) presented with symptoms of metastatic disease (headache in 2; pathological fracture of the femur in 1; and dysphagia – 1). Many of the patients (62.9%) presented after 2 years with large anterior neck swelling. PTC was commonly diagnosed in total thyroidectomy specimens (43.1%). Follicular variant of PTC was the commonest histological subtype (75.6%). Lymphovascular invasion was found in approximately 16.4% of the cases. Nine of the cases (7.8%) showed extra-glandular involvement.

Conclusion: The study found papillary thyroid cancer to be the commonest thyroid malignancy. There was a gradual decline in the number of cases over the period of study. Many of the patients were younger than 40 years of age and presented late with large palpable neck swellings. Approximately, 4.3% of patients presented cases with metastatic disease. [5]

Reference

[1] van Dalen, F., van Stevendaal, M., Fennemann, F., Verdoes, M. and Ilina, O., 2019. Molecular repolarisation of tumour-associated macrophages. Molecules24(1), p.9. (Web Link)

[2] Wen, S., Hou, Y., Fu, L., Xi, L., Yang, D., Zhao, M., Qin, Y., Sun, K., Teng, Y. and Liu, M., 2019. Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling. Cancer letters442, pp.320-332. (Web Link)

[3] Conlon, G.A. and Murray, G.I., 2019. Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis. The Journal of pathology247(5), pp.629-640. (Web Link)

[4] EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance Depner,H. zum Buttel,N. Böğürcü,A. M. Cuesta,M. R. Aburto,S. Seidel,F. Finkelmeier,F. Foss,J. Hofmann,K. Kaulich,S. Barbus,M. Segarra,G. Reifenberger,B. K. Garvalov,T. AckerA. Acker-Palmer

Nature Communications volume7, Article number: 12329 (2016)(Web Link)

[5] Der, E. M., Naaeder, S. B., Dakubo, J. N. and Gyasi, R. K. (2017) “Papillary Thyroid Cancer: A Histopathological Review in Accra, Ghana”, Journal of Advances in Medicine and Medical Research, 20(2), pp. 1-9. doi: 10.9734/BJMMR/2017/31822. (Web Link)

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