Epithelial cells require attachment to the extracellular matrix (ECM) for survival. However, during tumour progression and metastasis, cancerous epithelial cells must adapt to and survive in the absence of ECM. During the past 20 years, several cellular changes, including anoikis, have been shown to regulate cell viability when cells become detached from the ECM. In this Opinion article, we review in detail how cancer cells can overcome or take advantage of these specific processes. Gaining a better understanding of how cancer cells survive during detachment from the ECM will be instrumental in designing chemotherapeutic strategies that aim to eliminate ECM-detached metastatic cells.

Iron, an essential element used for a multitude of biochemical reactions, abnormally accumulates in the central nervous system of patients with multiple sclerosis (MS). The mechanisms of abnormal iron deposition in MS are not fully understood, nor do we know whether these deposits have adverse consequences, i.e., contribute to pathogenesis. With some exceptions, excess levels of iron are represented concomitantly in multiple deep gray matter structures often with bilateral representation, while in white matter pathological iron deposits are usually located at sites of inflammation that are associated with veins. These distinct spatial patterns suggest disparate mechanisms of iron accumulation between these regions. Iron has been postulated to promote disease activity in MS by various means: 1) iron can amplify the activated state of microglia resulting in the increased production of proinflammatory mediators; 2) excess intracellular iron deposits could promote mitochondria dysfunction; and 3) improperly managed iron could catalyze the production of damaging reactive oxygen species. The pathological consequences of abnormal iron deposits may be dependent on the affected brain region and/or accumulation process. Here we review putative mechanisms of enhanced iron uptake in MS and address the likely roles of iron in the pathogenesis of this disease.

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In order for cancer cells to survive during metastasis, they must overcome anoikis, a caspase-dependent cell death process triggered by extracellular matrix (ECM) detachment, and rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals used by cancer cells to facilitate their survival during metastasis remain poorly understood. We have discovered that oncogenic Ras facilitates the survival of ECM-detached cancer cells by using distinct effector pathways to regulate metabolism and block anoikis. Surprisingly, we find that while Ras-mediated phosphatidylinositol (3)-kinase signaling is critical for rectifying ECM-detachment-induced metabolic deficiencies, the critical downstream effector is serum and glucocorticoid-regulated kinase-1 (SGK-1) rather than Akt. Our data also indicate that oncogenic Ras blocks anoikis by diminishing expression of the phosphatase PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1), which promotes anoikis through the activation of p38 MAPK. Thus, our study represents a novel paradigm whereby oncogene-initiated signal transduction can promote the survival of ECM-detached cells through divergent downstream effectors. Cell Death and Differentiation (2016) 23, 1271-1282 doi:10.1038/cdd.2016 published online 26 February 2016 Cancer metastasis, the spread of cancer cells to distant parts of the body, accounts for~90% of cancer-related deaths and represents an inherently difficult clinical challenge.1,2 It has become clear that for successful metastasis to occur, cells must overcome a caspase-dependent cell death mechanism, anoikis, which is triggered by detachment from the extracellular matrix (ECM).3 In addition to anoikis evasion, cancer cells must also contend with anoikis-independent cellular alterations that can compromise cellular viability. 4 Chief among these alterations are metabolic deficiencies that are induced by ECM detachment. [5][6][7] These metabolic alterations involve deficiencies in ATP generation, elevated levels of reactive oxygen species, and the induction of autophagy. 6,8,9 Although recent studies have begun to unravel the strategies used by cancer cells to ameliorate metabolic deficiencies during ECM detachment, 10 the signal-transduction cascades responsible for regulating metabolism during ECM detachment in cancer cells remain almost entirely unexplored.The activation of oncogenic signaling pathways is critical to anchorage-independent growth and ultimately to the survival of a variety of distinct cancer cell types during ECM detachment. 4,11 Presumably, this oncogenic signaling is also necessary for resolving the aforementioned ECM-detachment-induced metabolic deficiencies. ErbB2 overexpression in mammary epithelial cells results in a stimulation of phosphatidylinositol (3)-kinase (PI(3)K)/Akt signaling to promote glucose uptake and ATP generation.6 These data raise the question as to how cancer cells that lack ErbB2 overexpression rectify metabolic deficiencies during ECM detachment. Does activation o...

Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.

Inflammatory breast cancer (IBC) is a highly metastatic and rare type of breast cancer, accounting for 2–6% of newly diagnosed breast cancer cases each year. The highly metastatic nature of IBC cells remains poorly understood. Here we describe our recent data regarding the ability of IBC cells to overcome anoikis.

Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Due to the inherent invasive nature of IBC cells, we hypothesized that IBC cells could evade detachment-induced apoptosis (anoikis), and rely on tightly regulated intracellular signaling pathways to do so. Here we demonstrate that in contrast to normal mammary epithelial cells, IBC cells robustly survive in ECM-detached conditions. ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment, suggesting overexpression/hyperactivation of these oncogenes is vital for IBC evasion of anoikis. Downstream of ErbB2 and EGFR, ERK/MAPK signaling was found to protect cells from anoikis by phosphorylating Bim-EL at serine 59. This phosphorylation of Bim-EL results in a physical interaction between Bim-EL, LC8, and Beclin-1 and prevents Bim-EL from localizing to the mitochondria and promoting cell death. Mutation of the serine 59 site results in increased cell death and a diminished capacity to form a protein complex with LC8 and Beclin-1. Bim-EL knockdown also rescued ECM-detachment-induced death in IBC cells, suggesting Bim-EL is necessary for the induction of anoikis in IBC cells. Interestingly, Bim-EL levels were found to be elevated in ECM-detached IBC cells and present in a significant percentage of IBC patient samples, despite their evasion of anoikis. Therefore, the sequestration of Bim-EL away the mitochondria provides a compelling rationale for how IBC cells survive in the presence of high Bim-EL levels. Furthermore, this mechanism provides a unique and novel opportunity for chemotherapeutic approaches aimed at freeing the already elevated Bim-EL levels from sequestration to specifically induce cell death in IBC cells. Citation Format: Cassandra Buchheit, Brittany Angarola, Allison Steiner, Kelsey Weigel, Zachary Schafer. Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1268. doi:10.1158/1538-7445.AM2015-1268

Host allelic variation controls the response to B. anthracis and the disease course of anthrax. Mouse strains with macrophages that are responsive to anthrax lethal toxin (LT) show resistance to infection while mouse strains with LT non-responsive macrophages succumb more readily. B6.CAST.11M mice have a region of chromosome 11 from the CAST/Ei strain (a LT responsive strain) introgressed onto a LT non-responsive C57BL/6J genetic background. Previously, B6.CAST.11M mice were found to exhibit a rapid inflammatory reaction to LT termed the early response phenotype (ERP), and displayed greater resistance to B. anthracis infection compared to C57BL/6J mice. Several ERP features (e.g., bloat, hypothermia, labored breathing, dilated pinnae vessels) suggested vascular involvement. To test this, Evan’s blue was used to assess vessel leakage and intravital microscopy was used to monitor microvascular blood flow. Increased vascular leakage was observed in lungs of B6.CAST.11M mice compared to C57BL/6J mice 1 hour after systemic administration of LT. Capillary blood flow was reduced in the small intestine mesentery without concomitant leukocyte emigration following systemic or topical application of LT, the latter suggesting a localized tissue mechanism in this response. Since LT activates the Nlrp1b inflammasome in B6.CAST.11M mice, the roles of inflammasome products, IL-1β and IL-18, were examined. Topical application to the mesentery of IL-1β but not IL-18 revealed pronounced slowing of blood flow in B6.CAST.11M mice that was not present in C57BL/6J mice. A neutralizing anti-IL-1β antibody suppressed the slowing of blood flow induced by LT, indicating a role for IL-1β in the response. Besides allelic differences controlling Nlrp1b inflammasome activation by LT observed previously, evidence presented here suggests that an additional genetic determinant(s) could regulate the vascular response to IL-1β. These results demonstrate that vessel leakage and alterations to blood flow are part of the rapid response in mice resistant to B. anthracis infection.