Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression

Buchheit, Cassandra L.; Weigel, Kelsey; Schafer, Zachary T.

doi:10.1038/nrc3789

Cited by 317 publications

(293 citation statements)

References 144 publications

Supporting

Mentioning

285

Contrasting

Unclassified

Order By: Relevance

“…The survival of cancer cells during ECM detachment requires rectifying ECM-detachment-induced loss of ATP generation (accomplished in this case by Ras-mediated SGK-1 activation) and blocking caspase activation (anoikis). 4 Given that we did not discern a role for Ras-mediated SGK-1 signaling in anoikis regulation (Figure 2f and Supplementary Figures S3B, S3C, S4B and S4C), we hypothesized that oncogenic Ras may use a distinct signaling pathway to block anoikis. Indeed, oncogenic Ras (either H-Ras or K-Ras) can effectively inhibit caspase-3/7 activation (Figure 5a) and promote cell viability (Figure 5b) during ECM detachment.…”

Section: Resultsmentioning

confidence: 99%

“…ATP generation) in addition to blocking caspase activation (anoikis) to survive during ECM detachment, 4 it is critically important to understand the precise molecular mechanisms involved in mediating both anoikis and metabolism. The data described here outline a unique, multifaceted signaling pathway operating downstream of oncogenic Ras to permit anoikis inhibition and stimulate ATP production ( Figure 8).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

et al. 2016

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…17 It has become clear that tumor progression and metastasis require cancer cells to inhibit anoikis, oftentimes through alterations in intracellular signaling pathways. [18][19][20] Interestingly, previous studies have shown that ErbB2 and EGFR, which are hyperactivated in a substantial percentage of IBC patients, 21 can effectively antagonize the anoikis program to facilitate anchorage-independent growth. [22][23][24][25][26][27][28] However, a detailed examination of the molecular mechanisms underlying anoikis inhibition in IBC cells has yet to be completed.…”

mentioning

confidence: 99%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Association of the Collagen Signature in the Tumor Microenvironment With Lymph Node Metastasis in Early Gastric Cancer

Chen

Jiang

et al. 2019

JAMA Surg

View full text Add to dashboard Cite

IMPORTANCE Lymph node status is the primary determinant in treatment decision making in early gastric cancer (EGC). Current evaluation methods are not adequate for estimating lymph node metastasis (LNM) in EGC. OBJECTIVE To develop and validate a prediction model based on a fully quantitative collagen signature in the tumor microenvironment to estimate the individual risk of LNM in EGC. DESIGN, SETTING, AND PARTICIPANTS This retrospective study was conducted from August 1, 2016, to May 10, 2018, at 2 medical centers in China (Nanfang Hospital and Fujian Provincial Hospital). Participants included a primary cohort (n = 232) of consecutive patients with histologically confirmed gastric cancer who underwent radical gastrectomy and received a T1 gastric cancer diagnosis from January 1, 2008, to December 31, 2012. Patients with neoadjuvant radiotherapy, chemotherapy, or chemoradiotherapy were excluded. An additional consecutive cohort (n = 143) who received the same diagnosis from January 1, 2011, to December 31, 2013, was enrolled to provide validation. Baseline clinicopathologic data of each patient were collected. Collagen features were extracted in specimens using multiphoton imaging, and the collagen signature was constructed. An LNM prediction model based on the collagen signature was developed and was internally and externally validated. MAIN OUTCOMES AND MEASURES The area under the receiver operating characteristic curve (AUROC) of the prediction model and decision curve were analyzed for estimating LNM. RESULTS In total, 375 patients were included. The primary cohort comprised 232 consecutive patients, in whom the LNM rate was 16.4% (n = 38; 25 men [65.8%] with a mean [SD] age of 57.82 [10.17] years). The validation cohort consisted of 143 consecutive patients, in whom the LNM rate was 20.9% (n = 30; 20 men [66.7%] with a mean [SD] age of 54.10 [13.19] years). The collagen signature was statistically significantly associated with LNM (odds ratio, 5.470; 95% CI, 3.315-9.026; P < .001). Multivariate analysis revealed that the depth of tumor invasion, tumor differentiation, and the collagen signature were independent predictors of LNM. These 3 predictors were incorporated into the new prediction model, and a nomogram was established. The model showed good discrimination in the primary cohort (AUROC, 0.955; 95% CI, 0.919-0.991) and validation cohort (AUROC, 0.938; 95% CI, 0.897-0.981). An optimal cutoff value was selected in the primary cohort, which had a sensitivity of 86.8%, a specificity of 93.3%, an accuracy of 92.2%, a positive predictive value of 71.7%, and a negative predictive value of 97.3%. The validation cohort had a sensitivity of 90.0%, a specificity of 90.3%, an accuracy of 90.2%, a positive predictive value of 71.1%, and a negative predictive value of 97.1%. Among the 375 patients, a sensitivity of 87.3%, a specificity of 92.1%, an accuracy of 91.2%, a positive predictive value of 72.1%, and a negative predictive value of 96.9% were found. CONCLUSIONS AND RELEVANCE This study's findings suggest th...

show abstract

Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression

Cited by 317 publications

References 144 publications

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

Association of the Collagen Signature in the Tumor Microenvironment With Lymph Node Metastasis in Early Gastric Cancer

Contact Info

Product

Resources

About