Emerging Biological Principles of Metastasis

The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.

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Roles of the immune system in cancer: from tumor initiation to metastatic progression.

Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance Given these attributes, the complex biological process of EMT has been heralded as a key hallmark of carcinogenesis, and targeting EMT pathways constitutes an attractive strategy for cancer treatment However, demonstrating the necessity of EMT for metastasis in vivo has been technically challenging, and recent efforts to demonstrate a functional contribution of EMT to metastasis have yielded unexpected results Therefore, determining the functional role of EMT in metastasis remains an area of active investigation Studies using improved lineage tracing systems, dynamic in vivo imaging, and clinically relevant in vivo models have the potential to uncover the direct link between EMT and metastasis This review focuses primarily on recent advances in and emerging concepts of the biology of EMT in metastasis in vivo and discusses future directions in the context of novel diagnostic and therapeutic opportunities

Epithelial Mesenchymal Transition in Tumor Metastasis

As the most commonly occurring cancer in women worldwide, breast cancer poses a formidable public health challenge on a global scale. Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast. While the risk factors associated with this cancer varies with respect to other cancers, genetic predisposition, most notably mutations in BRCA1 or BRCA2 gene, is an important causative factor for this malignancy. Breast cancers can begin in different areas of the breast, such as the ducts, the lobules, or the tissue in between. Within the large group of diverse breast carcinomas, there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites. It is important to distinguish between the various subtypes because they have different prognoses and treatment implications. As there are remarkable parallels between normal development and breast cancer progression at the molecular level, it has been postulated that breast cancer may be derived from mammary cancer stem cells. Normal breast development and mammary stem cells are regulated by several signaling pathways, such as estrogen receptors (ERs), HER2, and Wnt/β-catenin signaling pathways, which control stem cell proliferation, cell death, cell differentiation, and cell motility. Furthermore, emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially for triple-negative breast cancer. This review provides a comprehensive survey of the molecular, cellular and genetic aspects of breast cancer.

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis.

Immuno-oncology is an emerging field that has revolutionized cancer treatment Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies

Natural killer cells and other innate lymphoid cells in cancer.

Accumulating data suggest that metastatic dissemination often occurs early during tumour formation, but the mechanisms of early metastatic spread have not yet been addressed. Here, by studying metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible. Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours. Notably, we found that at least 80% of metastases were derived from early disseminated cancer cells. Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination.

Early dissemination seeds metastasis in breast cancer

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Early dissemination seeds metastasis in breast cancer