scholarly journals Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

2015 ◽  
Vol 112 (35) ◽  
pp. 10995-11000 ◽  
Author(s):  
J. Zachary Sanborn ◽  
Jongsuk Chung ◽  
Elizabeth Purdom ◽  
Nicholas J. Wang ◽  
Hojabr Kakavand ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Integration Site ◽  
Phylogenetic Analyses ◽  
Initial Response ◽  
Experimental Models ◽  
Cell Populations ◽  
Primary Tumors ◽  
Multiple Tumor ◽  
Tumor Virus ◽  
Multiple Cell

Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen from a common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.

scholarly journals Genetic tagging of tumor cells with retrovirus vectors: clonal analysis of tumor growth and metastasis in vivo.

1988 ◽  
Vol 8 (8) ◽  
pp. 3143-3149 ◽  
Author(s):  
B Korczak ◽  
I B Robson ◽  
C Lamarche ◽  
A Bernstein ◽  
R S Kerbel
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Mammary Adenocarcinoma ◽  
Cell Populations ◽  
Primary Tumors ◽  
Large Numbers ◽  
Retrovirus Vector

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines used were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with delta e delta pMoTN, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418r colonies were obtained at a frequency of 4 x 10(-3). Southern blot analysis of a number of clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal evolution of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10(5) cells from a pooled mixture of 3.6 x 10(2) G418r SP1HU9L or 10(4) G418r SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds or thousands of uniquely marked clones had been injected. In the case of the metastatic SP1HU9L cells, the nature of these "dominant" clones varied from one tumor to another. Analysis of a number of lung metastases revealed that a proportion of them were derived from dominant primary tumor clones and were composed of one, and sometimes two, distinct progenitors. In some animals, all the lung metastases were derived from a common progenitor clone, whereas in others, each metastatic nodule had a different progenitor. The results show the following. (i) Retrovirus vector infection can be used to introduce large numbers of unique and stable clonal markers into tumor cell populations. (ii) The progeny of a very limited number of clones dominate in advanced primary tumors. (iii) Mammary carcinoma metastases are of mono- or biclonal origin. The significance of the results is discussed.

Genetic tagging of tumor cells with retrovirus vectors: clonal analysis of tumor growth and metastasis in vivo

1988 ◽  
Vol 8 (8) ◽  
pp. 3143-3149
Author(s):  
B Korczak ◽  
I B Robson ◽  
C Lamarche ◽  
A Bernstein ◽  
R S Kerbel
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Mammary Adenocarcinoma ◽  
Cell Populations ◽  
Primary Tumors ◽  
Large Numbers ◽  
Retrovirus Vector

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines used were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with delta e delta pMoTN, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418r colonies were obtained at a frequency of 4 x 10(-3). Southern blot analysis of a number of clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal evolution of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10(5) cells from a pooled mixture of 3.6 x 10(2) G418r SP1HU9L or 10(4) G418r SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds or thousands of uniquely marked clones had been injected. In the case of the metastatic SP1HU9L cells, the nature of these "dominant" clones varied from one tumor to another. Analysis of a number of lung metastases revealed that a proportion of them were derived from dominant primary tumor clones and were composed of one, and sometimes two, distinct progenitors. In some animals, all the lung metastases were derived from a common progenitor clone, whereas in others, each metastatic nodule had a different progenitor. The results show the following. (i) Retrovirus vector infection can be used to introduce large numbers of unique and stable clonal markers into tumor cell populations. (ii) The progeny of a very limited number of clones dominate in advanced primary tumors. (iii) Mammary carcinoma metastases are of mono- or biclonal origin. The significance of the results is discussed.

scholarly journals Metastatic Esophageal Carcinoma Cells Exhibit Reduced Adhesion Strength and Enhanced Thermogenesis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1213
Author(s):  
Zihe Huo ◽  
Mariana Sá Santos ◽  
Astrid Drenckhan ◽  
Stefan Holland-Cunz ◽  
Jakob R. Izbicki ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Tumor Cells ◽  
Cell Lines ◽  
Adhesion Strength ◽  
Primary Tumor ◽  
Carcinoma Cell ◽  
Metastatic Potential ◽  
Primary Tumors ◽  
Metastatic Cell ◽  
Carcinoma Cell Lines

Despite continuous improvements in multimodal therapeutic strategies, esophageal carcinoma maintains a high mortality rate. Metastases are a major life-limiting component; however, very little is known about why some tumors have high metastatic potential and others not. In this study, we investigated thermogenic activity and adhesion strength of primary tumor cells and corresponding metastatic cell lines derived from two patients with metastatic adenocarcinoma of the esophagus. We hypothesized that the increased metastatic potential of the metastatic cell lines correlates with higher thermogenic activity and decreased adhesion strength. Our data show that patient-derived metastatic esophageal tumor cells have a higher thermogenic profile as well as a decreased adhesion strength compared to their corresponding primary tumor cells. Using two paired esophageal carcinoma cell lines of primary tumor and lymph nodes makes the data unique. Both higher specific thermogenesis profile and decreased adhesion strength are associated with a higher metastatic potential. They are in congruence with the clinical patient presentation. Understanding these functional, biophysical properties of patient derived esophageal carcinoma cell lines will enable us to gain further insight into the mechanisms of metastatic potential of primary tumors and metastases. Microcalorimetric evaluation will furthermore allow for rapid assessment of new treatment options for primary tumor and metastases aimed at decreasing the metastatic potential.

scholarly journals Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2148
Author(s):  
Francesco Ardito ◽  
Francesco Razionale ◽  
Lisa Salvatore ◽  
Tonia Cenci ◽  
Maria Vellone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Primary Tumor ◽  
Kras Mutation ◽  
Colorectal Tumor ◽  
Term Survival ◽  
Primary Tumors ◽  
Mutation Status ◽  
Primary Colorectal Tumor ◽  
Kras Mutation Status

If KRAS mutation status of primary colorectal tumor is representative of corresponding colorectal liver metastases (CRLM) mutational pattern, is controversial. Several studies have reported different rates of KRAS discordance, ranging from 4 to 32%. Aim of this study is to assess the incidence of discordance and its impact on overall survival (OS) in a homogenous group of patients. KRAS mutation status was evaluated in 107 patients resected for both primary colorectal tumor and corresponding CRLM at the same institution, between 2007 and 2018. Discordance rate was 15.9%. Its incidence varied according to the time interval between the two mutation analyses (p = 0.025; Pearson correlation = 0.2) and it was significantly higher during the first 6 months from the time of primary tumor evaluation. On multivariable analysis, type of discordance (wild-type in primary tumor, mutation in CRLM) was the strongest predictor of poor OS (p < 0.001). At multivariable logistic regression analysis, the number of CRLM >3 was an independent risk factor for the risk of KRAS discordance associated with the worst prognosis (OR = 4.600; p = 0.047). Results of our study suggested that, in the era of precision medicine, possibility of KRAS discordance should be taken into account within multidisciplinary management of patients with metastatic colorectal cancer.

Telomerase Expression Predicts Unfavorable Outcome in Osteosarcoma

2004 ◽  
Vol 22 (18) ◽  
pp. 3790-3797 ◽  
Author(s):  
Robert P. Sanders ◽  
Rachid Drissi ◽  
Catherine A. Billups ◽  
Najat C. Daw ◽  
Marcus B. Valentine ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Primary Tumor ◽  
Progression Free Survival ◽  
Outcome Analysis ◽  
Negative Group ◽  
Primary Tumors ◽  
Free Survival ◽  
Positive Group ◽  
Alternative Lengthening ◽  
Group 3

Purpose Osteosarcoma is distinct from most cancers in that the majority of osteosarcomas lack telomerase expression and use the alternative lengthening of telomeres (ALT) mechanism to maintain telomeres. Laboratory studies suggest that compared with ALT, telomerase expression is associated with increased tumor aggressiveness. We evaluated the clinical significance of telomerase expression in human osteosarcoma. Patients and Methods Fifty-six osteosarcomas from 51 patients treated at St Jude Children's Research Hospital between 1982 and 2003 were evaluated for telomerase enzyme activity, mRNA expression of the catalytic component of telomerase (TERT), and presence of the ALT pathway. Results Outcome analysis was based on TERT mRNA expression in the primary tumor samples from 44 patients. Fourteen primary tumors expressed TERT mRNA (32%; eight TERT only, six TERT and ALT) and 30 did not express TERT mRNA (68%; 29 ALT, one no ALT). Progression-free survival (PFS) was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 21.4% ± 9.5% v 63.7% ± 11.1%; P = .014). Likewise, overall survival was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 42.9% ± 12.2% v 70.0% ± 9.9%; P = .031). Among 31 patients with nonmetastatic disease at diagnosis, PFS was lower in the TERT-positive group compared with the TERT-negative group (3-year estimates, 33.3% ± 13.6% v 72.0% ± 11.5%; P = .092). Conclusion Telomerase expression in primary tumor samples is associated with decreased PFS and OS in patients with osteosarcoma. Additional studies are warranted to better define the clinical utility of this molecular marker.

Metastatic Tumors to the Spleen

2000 ◽  
Vol 124 (4) ◽  
pp. 526-530 ◽  
Author(s):  
K. Y. Lam ◽  
Victor Tang
Keyword(s):  
Primary Tumor ◽  
Metastatic Carcinoma ◽  
Chinese Patients ◽  
Primary Tumor Site ◽  
Primary Tumors ◽  
Secondary Tumors ◽  
Splenic Parenchyma ◽  
Pathologic Features ◽  
Splenic Metastases ◽  
Esophageal Carcinomas

Abstract Objective.—The clinicopathologic features of splenic metastases have seldom been investigated. The aim of this study was to evaluate the clinical and pathological impact of splenic metastases. Case Material.—We reviewed the clinical/autopsy records and pathologic features of 92 Chinese patients (58 men, 34 women) with secondary nonlymphoid splenic tumors recorded during a 25-year period. Results.—The incidence of splenic secondary tumors at autopsy was 0.6% and at splenectomy, 1.1%. The lesions were often seen in elderly patients (mean age, 60 years). Seven (8%) of the splenic lesions were symptomatic. The symptomatic splenic lesions, as compared with asymptomatic lesions, were bigger and were found more often in women and younger patients. Two patients experienced spontaneous splenic rupture because of metastatic carcinoma. Eighty-seven (95%) of the secondary splenic tumors were carcinomas. Lung was the most common primary tumor site (21%), followed by the stomach (16%), pancreas (12%), liver (9%), and colon (9%). Rarely reported sources of primary tumor, such as esophageal carcinomas, nasopharyngeal carcinoma, and choriocarcinoma, were also found. Splenic metastases could be identified macroscopically in 74 (80%) of our patients. Grossly, splenic metastases involved the splenic capsule (n = 8) or were solitary (n = 31), multiple (n = 30), or diffuse (n = 8) lesions in the splenic parenchyma. Isolated splenic metastases were noted in 5.3% of the metastases found at autopsy. Many of the metastatic lesions in the spleen were identified shortly after primary tumors were detected (mean latent period, 6.7 months). The time from diagnosis of the primary tumor to metastasis to the spleen was more than 2 years in 14 patients. Conclusions.—Splenic metastases are uncommon. A variety of clinical and pathologic patterns were noted in our series.

Genetic and immune divergence in pancreatic cancer lesions at the time of metastatic relapse compared to primary tumor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4140-4140
Author(s):  
Bereket Gebregziabher ◽  
Derek A. Oldridge ◽  
Emma E. Furth ◽  
Michael D. Feldman ◽  
Andrew J. Rech ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Adjuvant Chemotherapy ◽  
Rna Sequencing ◽  
Primary Tumor ◽  
Metastatic Tumors ◽  
Kras Mutations ◽  
Primary Tumors ◽  
Metastatic Relapse ◽  
Resected Tumor ◽  
First Relapse

4140 Background: Relapse of pancreatic ductal adenocarcinoma (PDA) is common even after complete resection and adjuvant therapy. Compared to the resected tumor, the biological characteristics of metastatic tumors at the time of first relapse are poorly understood. Methods: Whole-exome sequencing (WES) (250x) and bulk RNA sequencing were performed on samples from 30 patients with PDA. Paired primary tumor samples were obtained after R0 or R1 resection, and metastatic tumor samples were obtained by biopsy at the time of first relapse. 74.1% of patients had received adjuvant chemotherapy and radiation therapy, 7.4% had received adjuvant chemotherapy only, and 3.7% had received adjuvant radiation therapy only. Most common metastatic sites were liver and lung. The cohort was 60% male with a median age at diagnosis of 64 years. The vast majority of patients had stage IIA or IIB disease at diagnosis. Median disease-free survival was 481 days. Analysis used Freebayes (somatic variant calling), Kallisto (transcript quantification), Danaher et al. (cell type deconvolution), and antigen.garnish (neoantigen prediction). Results: High-quality WES and/or RNA sequencing were available for 27/30 patients. Among these were 16 pairs of primary and metastatic samples for WES and 15 paired samples for RNA sequencing. Median tumor purity was 32% (primary) and 42% (metastatic). KRAS mutations were present in 43/48 evaluable samples, with conserved KRAS mutations in 14/16 primary-metastatic pairs. Tumors were otherwise highly variable, with 13/16 patients developing oncogenic mutations in metastatic tumors that were undetected in primary tumors (BRCA1 [3/16], AKT3 [3/16], TP53 [2/16], ROS1 [2/16]). Overall, primary and metastatic tumors had similar tumor mutation burden and neoantigen production rate. However, neoantigens were highly variable at the peptide and gene level, with conservation rates of 2.73% and 11.57%, respectively, across primary-metastatic pairs. PDA transcriptomic subtype also differed across primary-metastatic pairs in all cases. Furthermore, metastatic tumors contained lower immune suppressive signal by transcripts and deconvolution (CTLA4: p = 0.0012, FOXP3: p = 0.0026, PDCD11: p = 0.012, regulatory T cells: p = 0.012), while myeloid cells were higher (CD33: p = 0.0067). Conclusions: With the exception of KRAS, metastatic PDA tumors at relapse contain new oncogenes, distinct neoantigens, and lower immune-suppressive signal compared to primary PDA tumors. These data suggest a potential clinical utility for tumor biopsies at the time of first metastatic relapse and caution against clinical decisions for relapsed, metastatic patients based solely on sequencing of the originally resected tumor.

An automated centrifugal microfluidic assay for whole blood fractionation and isolation of multiple cell populations using an aqueous two-phase system

Lab on a Chip ◽  
2021 ◽  
Author(s):  
Byeong-Ui Moon ◽  
Liviu Clime ◽  
Daniel Brassard ◽  
Alex Boutin ◽  
Jamal Daoud ◽  
...  
Keyword(s):  
Human Blood ◽  
Whole Blood ◽  
Cell Populations ◽  
Phase System ◽  
Two Phase ◽  
Microfluidic Platform ◽  
Aqueous Two Phase System ◽  
Separation Layers ◽  
Multiple Cell ◽  
On Chip

This paper describes an advanced on-chip whole human blood fractionation and cell isolation process combining an aqueous two-phase system to create complex separation layers with a centrifugal microfluidic platform to control and automate the assay.

scholarly journals RhoA localization with caveolin-1 regulates vascular contractions to serotonin

2012 ◽  
Vol 303 (9) ◽  
pp. R959-R967 ◽  
Author(s):  
Daniel W. Nuno ◽  
Sarah K. England ◽  
Kathryn G. Lamping
Keyword(s):  
Lipid Rafts ◽  
Rho Kinase ◽  
Initial Response ◽  
Cell Types ◽  
Smooth Muscle Contraction ◽  
High Density ◽  
Low Density ◽  
Density Fractions ◽  
Caveolin 1 ◽  
Multiple Cell

Vascular smooth muscle contraction occurs following an initial response to an increase in intracellular calcium concentration and a sustained response following increases in the sensitivity of contractile proteins to calcium (calcium sensitization). This latter process is regulated by the rhoA/rho kinase pathway and activated by serotonin. In multiple cell types, signaling molecules compartmentalize within caveolae to regulate their activation. We hypothesized that serotonin differentially compartmentalizes rhoA within caveolar versus noncaveolar lipid rafts to regulate sustained vascular contractions. To test this hypothesis, we measured aortic contractions in response to serotonin in wild-type (WT) and cav-1-deficient mice (cav-1 KO). RhoA-dependent contractions in response to serotonin were markedly augmented in arteries from cav-1 KO mice despite a modest reduction in rhoA expression compared with WT. We found that under basal conditions, rhoA in WT arteries was primarily localized within high-density sucrose gradient fractions but temporally shifted to low-density fractions in response to serotonin. In contrast, rhoA in cav-1 KO arteries was primarily in low-density fractions and shifted to high-density fractions in a similar timeframe as that seen in WT mice. We conclude that localization of rhoA to caveolar versus noncaveolar lipid rafts differentially regulates its activation and contractions to rhoA-dependent agonists with greater activation associated with its localization to noncaveolar rafts. Disruption of rhoA localization within caveolae may contribute to increased activation and enhanced vascular contractions in cardiovascular disease.

Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin.

1995 ◽  
Vol 13 (8) ◽  
pp. 2094-2103 ◽  
Author(s):  
J L Abbruzzese ◽  
M C Abbruzzese ◽  
R Lenzi ◽  
K R Hess ◽  
M N Raber
Keyword(s):  
Computed Tomography ◽  
Ovarian Cancer ◽  
Primary Tumor ◽  
Radiographic Finding ◽  
Diagnostic Evaluation ◽  
Survival Duration ◽  
Rank Test ◽  
Diagnostic Strategy ◽  
Primary Tumors ◽  
Specific Patient

PURPOSE Diagnostic strategies designed to identify the underlying primary malignancies in patients with unknown primary tumors (UPTs) have relied on retrospective analyses. We analyzed 879 consecutive patients referred with suspected UPTs to determine the yield and cost of a limited diagnostic evaluation, assess the contribution of specific studies to diagnosis, and analyze the survival patterns of patients in whom the primary tumor was diagnosed. PATIENTS AND METHODS Data from patients with a suspected UPT were entered into a computerized data base, and the patients underwent a predefined limited diagnostic evaluation. Primary malignancies were diagnosed by pathologic review alone or by pathologic criteria plus a physical or radiographic finding. Survival was measured from diagnosis, estimated using the Kaplan-Meier method, and compared using the Cox-Mantel log-rank test. RESULTS A primary tumor was found in 179 of 879 patients (20%). The survival duration of patients in whom the primary tumor was diagnosed was superior to that of patients in whom the primary tumor remained unknown. Specific patient subsets contributed most to the improved survival duration of the group in which the primary tumor was found, including lymphoma patients diagnosed solely by pathologic criteria and female patients with primary breast or ovarian cancer. The cost of diagnosis was mostly due to the extensive use of computed tomography. Except for ovarian cancer, computed tomography rarely identified treatable primary tumors. CONCLUSION The limited diagnostic evaluation used in this study identified patients with treatable malignancies and increased the survival duration of a population of suspected UPT patients. Primary malignancies with the best survival can be diagnosed through careful pathologic review and focused evaluations for breast and ovarian cancer in women.

Sign in / Sign up

Export Citation Format

Share Document