Fluorescence in Situ Hybridization Markers for Prediction of Cervical Lymph Node Metastases

Wangsa, Darawalee; Heselmeyer‐Haddad, Kerstin; Ried, Patricia; Eriksson, Ejnar; Schäffer, Alejandro A.; Morrison, Larry E.; Luo, Juhua; Auer, Gert; Munck‐Wikland, Eva; Ried, Thomas; Lundqvist, Elisabeth Åvall

doi:10.2353/ajpath.2009.090289

Cited by 21 publications

(38 citation statements)

References 41 publications

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“…Our data show that in these patients, LAMP3 expression is regulated by both genetic gains/amplifications of LAMP3 and tumor hypoxia. Similar to other studies in cervix cancer (38), approximately 40% of all patients showed copy number aberrations and this was associated with increased LAMP3 mRNA and protein expression. However, in the other 60% with no copy number aberrations, we found that hypoxia was strongly and significantly associated with LAMP3 expression.…”

Section: Discussionsupporting

confidence: 72%

Hypoxic Activation of the PERK/eIF2α Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3

Mujčić

Nagelkerke

Rouschop

et al. 2013

Clinical Cancer Research

102

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Purpose: Conditions of poor oxygenation (hypoxia) are present in many human tumors, including cervix cancer, and are associated with increased risk of metastasis and poor prognosis. Hypoxia is a potent activator of the PERK/eIF2a signaling pathway, a component of the unfolded protein response (UPR) and an important mediator of hypoxia tolerance and tumor growth. Here, the importance of this pathway in the metastasis of human cervix carcinoma was investigated.Experimental Design: Amplification and expression of LAMP3, a UPR metastasis-associated gene, was examined using FISH and immunofluorescence in a cohort of human cervix tumors from patients who had received oxygen needle electrode tumor oxygenation measurements. To evaluate the importance of this pathway in metastasis in vivo, we constructed a series of inducible cell lines to interfere with PERK signaling during hypoxia and used these in an orthotopic cervix cancer model of hypoxia-driven metastasis.Results: We show that LAMP3 expression in human cervix tumors is augmented both by gene copy number alterations and by hypoxia. Induced disruption of PERK signaling in established orthotopic xenografts resulted in complete inhibition of hypoxia-induced metastasis to the lymph nodes. This is due, in part, to a direct influence of the UPR pathway on hypoxia tolerance. However, we also find that LAMP3 is a key mediator of hypoxia-driven nodal metastasis, through its ability to promote metastatic properties including cell migration.Conclusion: These data suggest that the association between hypoxia, metastasis, and poor prognosis is due, in part, to hypoxic activation of the UPR and expression of LAMP3.

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Section: Discussionsupporting

confidence: 72%

Hypoxic Activation of the PERK/eIF2α Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3

Mujčić

Nagelkerke

Rouschop

et al. 2013

Clinical Cancer Research

102

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“…Tumor expression of specific AMPK α, β, and γ subunits in relation to cancer outcomes has been explored in patients with melanoma (87), kidney cancer (85, 86), breast cancer (74), cervical cancer (88), lymphoma (89), ovarian cancer (84, 90, 91), lung cancer (82), and colorectal cancer (92). Total AMPKα1 protein expression, which captures both phosphorylated and non-phosphorylated AMPKα1, was associated with improved overall and disease-specific survival among 128 melanoma patients (87).…”

Section: Ampk Role In Cancer: Human Studiesmentioning

confidence: 99%

Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies

Zadra

Batista

Loda

2015

Molecular Cancer Research

176

162

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The precise role of 5′AMP-activated kinase (AMPK) in cancer and its potential as a therapeutic target is controversial. While it is well established that activation of this energy sensor inhibits the main anabolic processes that sustain cancer cell proliferation and growth, AMPK activation can confer on cancer cells the plasticity to survive under metabolic stress such as hypoxia and glucose deprivation, which are commonly observed in fast growing tumors. Thus, AMPK is referred to as both a “conditional” tumor suppressor and “contextual” oncogene. To add a further layer of complexity, AMPK activation in human cancer tissues and its correlation with tumor aggressiveness and progression appears to vary in different contexts. The current review discusses the different faces of this metabolic regulator, the therapeutic implications of its modulation and provides an overview of the most relevant data available on AMPK activation and AMPK activating drugs in human studies.

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“…3,4 The gain of 5p is frequently present in high-grade cervical squamous intraepithelial lesion specimens and is associated with marked dysplasia and cancer. 2,4 These data indicate that the presence of extra copies of these chromosomal loci drives the initial steps of cervical carcinogenesis. [1][2][3][4] In this case, the Cervical DNA Dtex test was used to enumerate genomic copy number for 3q26, 5p15, and centromere 7.…”

Section: Pathologic Findingsmentioning

confidence: 91%

“…2,4 These data indicate that the presence of extra copies of these chromosomal loci drives the initial steps of cervical carcinogenesis. [1][2][3][4] In this case, the Cervical DNA Dtex test was used to enumerate genomic copy number for 3q26, 5p15, and centromere 7. The results showed increased copy number for these markers, indicating extensive DNA damage within these critical regions of the genome.…”

Section: Pathologic Findingsmentioning

confidence: 91%

“…DNA damage at 3q26 and 5p15 is associated with cervical carcinogenesis. [1][2][3][4] The threshold value for a negative Dtex result is the presence of less than 1% abnormal cells. The 2006 ASCCP guidelines suggest 3 possible options for the management of a patient with an Atypical Glandular Cells Papanicolaou test with colposcopic biopsy showing CIN 1 and a negative endocervical curettage: (1) excisional procedure; (2) review of all findings; or (3) follow-up with subsequent Papanicolaou and colposcopy in 6 months.…”

mentioning

confidence: 99%

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Cervical Adenocarcinoma Identification by Testing for Chromosomal Abnormalities

Dittus¹,

Dudley²,

Upender³

et al. 2013

Archives of Pathology & Laboratory Medicine

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We report on a case of cervical adenocarcinoma in situ in a 42-year-old woman with a history of human papillomavirus infection. Repeat cytology, human papillomavirus testing, and colposcopy failed to identify the lesion. Testing of the cervical cell DNA identified chromosomal abnormalities, prompting a cervical cone biopsy, which identified adenocarcinoma in situ. (Arch Pathol Lab Med. 2013;137:1829-1831 doi: 10.5858/arpa.2012-0499-CR) REPORT OF A CASE A 42-year-old woman, gravida 1, para 1, visited her new gynecologist for routine gynecologic care. Papanicolaou testing performed at her visit revealed atypical squamous cellsunknown significance with rare atypical cells. Reflex human papillomavirus (HPV) testing findings were positive for high-risk subtypes. The patient indicated her previous Papanicolaou tests had been normal. A decision was made to do a follow-up Papanicolaou test in 6 months because of the provided clinical history and because only rare atypical cells were seen on this Papanicolaou test.At the 6-month follow-up, Papanicolaou testing revealed atypical endocervical cells, not otherwise specified. Because of a repeat abnormal Papanicolaou result and a history of testing positive for HPV, the patient was scheduled for colposcopy and endocervical curettage. Multiple biopsies (8) of the transformation zone and acetowhite epithelium were taken during an adequate colposcopy procedure. Pathology revealed cervical intraepithelial neoplasia (CIN) 1, and endocervical curettage showed squamous metaplasia. This was done in accordance with American Congress of Obstetricians and Gynecologists (ACOG) and American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines.A Cervical DNA Dtex test (NeoDiagnostix, Rockville, Maryland) for chromosomal abnormalities was performed on the second Papanicolaou specimen because of the lack of correlation between histology and cytology. This test showed significant DNA damage, with 13% of the cells being abnormal (Figure). DNA damage at 3q26 and 5p15 is associated with cervical carcinogenesis.1-4 The threshold value for a negative Dtex result is the presence of less than 1% abnormal cells. The 2006 ASCCP guidelines suggest 3 possible options for the management of a patient with an Atypical Glandular Cells Papanicolaou test with colposcopic biopsy showing CIN 1 and a negative endocervical curettage: (1) excisional procedure; (2) review of all findings; or (3) follow-up with subsequent Papanicolaou and colposcopy in 6 months. With the advantage of the additional information provided by the Cervical DNA Dtex test, the clinician chose (1), the first option. The physician decided to do a cold knife conization to rule out a more severe lesion. The cone biopsy, excised to a depth of 2.8 cm, revealed adenocarcinoma in situ (AIS) without squamous lesions. The pathology report also commented that the tissue test result was strongly positive for p16 and Ki-67, which are shown to be markedly elevated with AIS.5 As per gynecologic oncologist recommendation, the patient unde...

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Fluorescence in Situ Hybridization Markers for Prediction of Cervical Lymph Node Metastases

Cited by 21 publications

References 41 publications

Hypoxic Activation of the PERK/eIF2α Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3

Hypoxic Activation of the PERK/eIF2α Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3

Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies

Cervical Adenocarcinoma Identification by Testing for Chromosomal Abnormalities

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