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Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis.
Stoletov K, Willetts L, Paproski RJ, Bond DJ, Raha S, Jovel J, Adam B, Robertson AE, Wong F, Woolner E, Sosnowski DL, Bismar TA, Wong GK, Zijlstra A, Lewis JD
(2018) Nat Commun 9: 2343
MeSH Terms: Animals, Cell Line, Tumor, Cell Movement, Chick Embryo, Collagen, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Nude, Mice, SCID, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Transplantation, Phenotype, Prostatic Neoplasms, RNA Interference, RNA, Small Interfering
Show Abstract · Added April 10, 2019
Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.
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MeSH Terms
ERα-Mediated Nuclear Sequestration of RSK2 Is Required for ER Breast Cancer Tumorigenesis.
Ludwik KA, McDonald OG, Brenin DR, Lannigan DA
(2018) Cancer Res 78: 2014-2025
MeSH Terms: Animals, Breast Neoplasms, Carcinogenesis, Cell Nucleus, Estrogen Receptor alpha, Female, Humans, MCF-7 Cells, Mice, Mice, Inbred C57BL, Neoplasm Invasiveness, Ribosomal Protein S6 Kinases, 90-kDa
Show Abstract · Added July 20, 2018
Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple and models of estrogen receptor-positive (ER) breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N terminus to activate a proneoplastic transcriptional network critical to the ER lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies. Nuclear accumulation of active RSK drives a protumorigenic transcriptional program and renders ER breast cancer susceptible to endocrine-based therapies. .
©2018 American Association for Cancer Research.
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12 MeSH Terms
Nodal Disease in Rectal Cancer Patients With Complete Tumor Response After Neoadjuvant Chemoradiation: Danger Below Calm Waters.
Baucom RB, Maguire LH, Kavalukas SL, Geiger TM, Ford MM, Muldoon RL, Hopkins MB, Hawkins AT
(2017) Dis Colon Rectum 60: 1260-1266
MeSH Terms: Adenocarcinoma, Case-Control Studies, Chemoradiotherapy, Combined Modality Therapy, Female, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Invasiveness, Neoplasm Staging, Neoplasm, Residual, Rectal Neoplasms, Retrospective Studies, Risk Factors, Survival Rate, Treatment Outcome, United States
Show Abstract · Added December 14, 2017
BACKGROUND - A subset of patients with rectal cancer who undergo neoadjuvant chemoradiation therapy will develop a complete pathologic tumor response. Complete nodal response is not universal in these patients and is difficult to assess clinically. Quantifying the risk of nodal disease would allow for targeted therapy with either radical resection or "watchful waiting."
OBJECTIVE - This study aimed to identify risk factors for residual nodal disease in ypT0 rectal adenocarcinoma.
DESIGN - This is a retrospective case control study.
SETTINGS - The National Cancer Database 2006 to 2014 was used to identify patients for this study.
PATIENTS - Patients with stage II/III rectal adenocarcinoma who completed chemoradiation therapy followed by resection and who had ypT0 tumors were included. Patients with metastatic disease and <2 lymph nodes evaluated were excluded. Patients were divided into 2 groups: node positive and node negative.
MAIN OUTCOME MEASURES - The main outcome was nodal disease. The secondary outcome was overall survival.
RESULTS - A total of 42,257 patients with stage II/III rectal cancer underwent chemoradiation therapy and radical resection; 4170 (9.9%) patients had ypT0 tumors and 395 (9.5%) were node positive. Of patients with clinically node-negative disease (ie, pretreatment imaging), 6.2% were node positive after chemoradiation therapy and resection. In multivariable analysis, factors predictive of nodal disease included increasing (pretreatment) clinical N-stage, high tumor grade (3/4), perineural invasion, and lymphovascular invasion. Higher clinical T-stage was inversely associated with residual nodal disease. Overall 5-year survival was significantly different between patients with ypN0, ypN1, and ypN2 disease (87.4%, 82.2%, and 62.5%, p = 0.002).
LIMITATIONS - This study was limited by the lack of clinical detail in the database and the inability to assess recurrence.
CONCLUSIONS - Ten percent of patients with ypT0 tumors had positive nodes after chemoradiation therapy and resection. Factors associated with residual nodal disease included clinical nodal disease at diagnosis and poor histologic features. Patients with any of these features should consider radical resection regardless of tumor response. Others could be suitable for "watchful waiting" strategies. See Video Abstract at http://links.lww.com/DCR/A458.
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19 MeSH Terms
Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, Washington MK, Shi C, Franco OE, Weaver AM, Hayward SW, Li D, Webb DJ
(2017) J Cell Biol 216: 3799-3816
MeSH Terms: Cancer-Associated Fibroblasts, Cell Communication, Cell Line, Tumor, Cell Movement, Coculture Techniques, Extracellular Matrix, Fibronectins, Humans, Integrin alpha5beta1, Male, Mechanotransduction, Cellular, Neoplasm Invasiveness, Nonmuscle Myosin Type IIA, Prostatic Neoplasms, RNA Interference, Receptor, Platelet-Derived Growth Factor alpha, Time Factors, Transfection, Tumor Cells, Cultured, Tumor Microenvironment
Show Abstract · Added March 14, 2018
Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.
© 2017 Erdogan et al.
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20 MeSH Terms
Gallbladder Cancer Presenting with Jaundice: Uniformly Fatal or Still Potentially Curable?
Tran TB, Norton JA, Ethun CG, Pawlik TM, Buettner S, Schmidt C, Beal EW, Hawkins WG, Fields RC, Krasnick BA, Weber SM, Salem A, Martin RCG, Scoggins CR, Shen P, Mogal HD, Idrees K, Isom CA, Hatzaras I, Shenoy R, Maithel SK, Poultsides GA
(2017) J Gastrointest Surg 21: 1245-1253
MeSH Terms: Aged, Bilirubin, Blood Vessels, CA-19-9 Antigen, Drainage, Female, Gallbladder Neoplasms, Humans, Jaundice, Obstructive, Lymphatic Vessels, Male, Middle Aged, Neoplasm Invasiveness, Postoperative Complications, Reoperation, Survival Rate, United States
Show Abstract · Added April 10, 2018
BACKGROUND - Jaundice as a presenting symptom of gallbladder cancer has traditionally been considered to be a sign of advanced disease, inoperability, and poor outcome. However, recent studies have demonstrated that a small subset of these patients can undergo resection with curative intent.
METHODS - Patients with gallbladder cancer managed surgically from 2000 to 2014 in 10 US academic institutions were stratified based on the presence of jaundice at presentation (defined as bilirubin ≥4 mg/ml or requiring preoperative biliary drainage). Perioperative morbidity, mortality, and overall survival were compared between jaundiced and non-jaundiced patients.
RESULTS - Of 400 gallbladder cancer patients with available preoperative data, 108 (27%) presented with jaundice while 292 (73%) did not. The fraction of patients who eventually underwent curative-intent resection was much lower in the presence of jaundice (n = 33, 30%) than not (n = 218, 75%; P < 0.001). Jaundiced patients experienced higher perioperative morbidity (69 vs. 38%; P = 0.002), including a much higher need for reoperation (12 vs. 1%; P = 0.003). However, 90-day mortality (6.5 vs. 3.6%; P = 0.35) was not significantly higher. Overall survival after resection was worse in jaundiced patients (median 14 vs. 32 months; P < 0.001). Further subgroup analysis within the jaundiced patients revealed a more favorable survival after resection in the presence of low CA19-9 < 50 (median 40 vs. 12 months; P = 0.003) and in the absence of lymphovascular invasion (40 vs. 14 months; P = 0.014).
CONCLUSION - Jaundice is a powerful preoperative clinical sign of inoperability and poor outcome among gallbladder cancer patients. However, some of these patients may still achieve long-term survival after resection, especially when preoperative CA19-9 levels are low and no lymphovascular invasion is noted pathologically.
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Matrix stiffening promotes a tumor vasculature phenotype.
Bordeleau F, Mason BN, Lollis EM, Mazzola M, Zanotelli MR, Somasegar S, Califano JP, Montague C, LaValley DJ, Huynh J, Mencia-Trinchant N, Negrón Abril YL, Hassane DC, Bonassar LJ, Butcher JT, Weiss RS, Reinhart-King CA
(2017) Proc Natl Acad Sci U S A 114: 492-497
MeSH Terms: Animals, Biomechanical Phenomena, Cattle, Cells, Cultured, Chick Embryo, Collagen, Extracellular Matrix, Female, Human Umbilical Vein Endothelial Cells, Humans, Mammary Neoplasms, Experimental, Matrix Metalloproteinases, Mice, Microvessels, Neoplasm Invasiveness, Neovascularization, Pathologic, Phenotype, Tumor Microenvironment, Vascular Stiffness
Show Abstract · Added April 10, 2019
Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell-cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery.
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The Mechanics of Single Cell and Collective Migration of Tumor Cells.
Lintz M, Muñoz A, Reinhart-King CA
(2017) J Biomech Eng 139:
MeSH Terms: Animals, Cell Movement, Computer Simulation, Extracellular Matrix, Humans, Mechanotransduction, Cellular, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis
Show Abstract · Added April 10, 2019
Metastasis is a dynamic process in which cancer cells navigate the tumor microenvironment, largely guided by external chemical and mechanical cues. Our current understanding of metastatic cell migration has relied primarily on studies of single cell migration, most of which have been performed using two-dimensional (2D) cell culture techniques and, more recently, using three-dimensional (3D) scaffolds. However, the current paradigm focused on single cell movements is shifting toward the idea that collective migration is likely one of the primary modes of migration during metastasis of many solid tumors. Not surprisingly, the mechanics of collective migration differ significantly from single cell movements. As such, techniques must be developed that enable in-depth analysis of collective migration, and those for examining single cell migration should be adopted and modified to study collective migration to allow for accurate comparison of the two. In this review, we will describe engineering approaches for studying metastatic migration, both single cell and collective, and how these approaches have yielded significant insight into the mechanics governing each process.
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Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma.
Cannonier SA, Gonzales CB, Ely K, Guelcher SA, Sterling JA
(2016) Oncotarget 7: 76062-76075
MeSH Terms: Animals, Bone and Bones, Carcinoma, Squamous Cell, Cell Line, Tumor, Disease Models, Animal, Gene Expression, Hedgehog Proteins, Heterografts, Humans, Mice, Mouth Neoplasms, Neoplasm Invasiveness, Nuclear Proteins, Parathyroid Hormone-Related Protein, Signal Transduction, Transforming Growth Factor beta, Zinc Finger Protein Gli2
Show Abstract · Added April 26, 2017
Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC invasion into the lymph nodes and mandible correlates with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly and induce bone destruction. While survival rates have increased 12% over the last 20 years, this improvement is attributed to general advances in prevention, earlier detection, and updated treatments. Additionally, despite decades of research, the molecular mechanisms of OSCC invasion into the mandible are not well understood. Parathyroid Hormone-related Protein (PTHrP), has been shown to be essential for mandibular invasion in OSCC animal models, and our previous studies demonstrate that the transcription factor Gli2 increases PTHrP expression in tumor metastasis to bone. In OSCC, we investigated regulators of Gli2, including Hedgehog, TGFβ, and Wnt signaling to elucidate how PTHrP expression is controlled. Here we show that canonical Hedgehog and TGFβ signaling cooperate to increase PTHrP expression and mandibular invasion in a Gli2-dependent manner. Additionally, in an orthotopic model of mandibular invasion, inhibition of Gli2 using shRNA resulted in a significant decrease of both PTHrP expression and bony invasion. Collectively, our findings demonstrate that multiple signaling pathways converge on Gli2 to mediate PTHrP expression and bony invasion, highlighting Gli2 as a therapeutic target to prevent bony invasion in OSCC.
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Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis.
Boutaud O, Sosa IR, Amin T, Oram D, Adler D, Hwang HS, Crews BC, Milne G, Harris BK, Hoeksema M, Knollmann BC, Lammers PE, Marnett LJ, Massion PP, Oates JA
(2016) Cancer Prev Res (Phila) 9: 855-865
MeSH Terms: Adenocarcinoma, Adult, Aspirin, Cell Line, Tumor, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Dinoprostone, Female, Humans, Male, Neoplasm Invasiveness
Show Abstract · Added January 29, 2018
Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E (PGE) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE biosynthesis. We show that low-dose aspirin inhibits systemic PGE biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE production by the platelet-tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855-65. ©2016 AACR.
©2016 American Association for Cancer Research.
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Advanced Intestinal Cancers often Maintain a Multi-Ancestral Architecture.
Zahm CD, Szulczewski JM, Leystra AA, Paul Olson TJ, Clipson L, Albrecht DM, Middlebrooks M, Thliveris AT, Matkowskyj KA, Washington MK, Newton MA, Eliceiri KW, Halberg RB
(2016) PLoS One 11: e0150170
MeSH Terms: Adenocarcinoma, Adenoma, Animals, Carcinoma in Situ, Cell Lineage, Cell Transformation, Neoplastic, Clone Cells, Disease Models, Animal, Disease Progression, Evolution, Molecular, Fatty Acid-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Genes, APC, Genes, Reporter, Integrases, Intestinal Mucosa, Intestinal Neoplasms, Luminescent Proteins, Male, Mice, Mice, Inbred C57BL, Models, Biological, Mosaicism, Neoplasm Invasiveness, Neoplastic Stem Cells, RNA, Untranslated, Rats, Transgenes, Tumor Microenvironment
Show Abstract · Added April 12, 2016
A widely accepted paradigm in the field of cancer biology is that solid tumors are uni-ancestral being derived from a single founder and its descendants. However, data have been steadily accruing that indicate early tumors in mice and humans can have a multi-ancestral origin in which an initiated primogenitor facilitates the transformation of neighboring co-genitors. We developed a new mouse model that permits the determination of clonal architecture of intestinal tumors in vivo and ex vivo, have validated this model, and then used it to assess the clonal architecture of adenomas, intramucosal carcinomas, and invasive adenocarcinomas of the intestine. The percentage of multi-ancestral tumors did not significantly change as tumors progressed from adenomas with low-grade dysplasia [40/65 (62%)], to adenomas with high-grade dysplasia [21/37 (57%)], to intramucosal carcinomas [10/23 (43%]), to invasive adenocarcinomas [13/19 (68%)], indicating that the clone arising from the primogenitor continues to coexist with clones arising from co-genitors. Moreover, neoplastic cells from distinct clones within a multi-ancestral adenocarcinoma have even been observed to simultaneously invade into the underlying musculature [2/15 (13%)]. Thus, intratumoral heterogeneity arising early in tumor formation persists throughout tumorigenesis.
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30 MeSH Terms