Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2014

Open Access 01-12-2014 | Research

Metabolic phenotypes in primary unknown metastatic carcinoma

Authors: Hye Min Kim, Do Hee Kim, Woo Hee Jung, Ja Seung Koo

Published in: Journal of Translational Medicine | Issue 1/2014

Login to get access

Abstract

Background

The purpose of this study is to evaluate expression of metabolism-related proteins in primary unknown metastatic carcinoma (PUMC) and associated implications for treatment.

Methods

A tissue microarray containing 77 cases of PUMC was constructed and immunohistochemical staining was used to evaluate expression of the following proteins: Glycolysis-related: Glut-1, carbonic anhydrase (CA) IX, and monocarboxylate transporter (MCT) 4; Glutaminolysis-related: glutaminase1 (GLS1), glutamate dehydrogenase (GDH), and amino acid transporter-2 (ASCT2); and Mitochondrial-related: ATP synthase, succinate dehydrogenase (SDH)A, and SDHB. The association between immunohistochemical staining results and clinicopathologic parameters was evaluated.

Results

The expression of metabolism-related proteins was different depending on the histologic subtype. Compared to other subtypes, squamous cell carcinomas (SQ) expressed more Glut-1 (p = 0.028), while adenocarcinomas (AD) expressed more SDHB in the stroma (p = 0.025). The expression of metabolism-related proteins was also different depending on the clinical subtypes. Glut-1 was expressed most in the nodal type and the least in carcinomatosis type, when compared to other subtypes (p = 0.021). The metabolic phenotypes also showed other trends: when the stroma showed no glutaminolysis, the tumor mostly invaded lymph node, bone, and brain, while the tumor invaded regions other than lymph node, bone, and brain when the stroma showed glutaminolysis (p = 0.003). When the stroma showed the mitochondrial metabolic type, the histologic subtype was mainly AD, but the non-mitochondrial type was associated more with SQ (P = 0.049).

Conclusion

For PUMC, the expression of metabolism-related proteins, such as Glut-1 and SDHB, differs in the tumor or stroma depending on the clinical and histologic tumor subtype.
Appendix
Available only for authorised users
Literature
1.
Pavlidis N, Fizazi K: Cancer of unknown primary (CUP). Crit Rev Oncol Hematol. 2005, 54: 243-250. 10.1016/j.critrevonc.2004.10.002.CrossRefPubMed
2.
Haskell CM, Cochran AJ, Barsky SH, Steckel RJ: Metastasis of unknown origin. Curr Probl Cancer. 1988, 12: 5-58. 10.1016/S0147-0272(88)80007-2.CrossRefPubMed
3.
Krementz ET, Cerise EJ, Foster DS, Morgan LR: Metastases of undetermined source. Curr Probl Cancer. 1979, 4: 4-37.CrossRefPubMed
4.
Lembersky BC, Thomas LC: Metastases of unknown primary site. Med Clin North Am. 1996, 80: 153-171. 10.1016/S0025-7125(05)70433-8.CrossRefPubMed
5.
van de Wouw AJ, Jansen RL, Speel EJ, Hillen HF: The unknown biology of the unknown primary tumour: a literature review. Ann Oncol. 2003, 14: 191-196. 10.1093/annonc/mdg068.CrossRefPubMed
6.
Warburg O: On the origin of cancer cells. Science. 1956, 123: 309-314. 10.1126/science.123.3191.309.CrossRefPubMed
7.
Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E: Energy metabolism in tumor cells. FEBS J. 2007, 274: 1393-1418. 10.1111/j.1742-4658.2007.05686.x.CrossRefPubMed
8.
9.
Won KY, Kim GY, Kim YW, Song JY, Lim SJ: Clinicopathologic correlation of beclin-1 and bcl-2 expression in human breast cancer. Hum Pathol. 2010, 41: 107-112. 10.1016/j.humpath.2009.07.006.CrossRefPubMed
10.
Airley R, Loncaster J, Davidson S, Bromley M, Roberts S, Patterson A, Hunter R, Stratford I, West C: Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin Cancer Res. 2001, 7: 928-934.PubMed
11.
Cantuaria G, Fagotti A, Ferrandina G, Magalhaes A, Nadji M, Angioli R, Penalver M, Mancuso S, Scambia G: GLUT-1 expression in ovarian carcinoma: association with survival and response to chemotherapy. Cancer. 2001, 92: 1144-1150. 10.1002/1097-0142(20010901)92:5<1144::AID-CNCR1432>3.0.CO;2-T.CrossRefPubMed
12.
Endo M, Tateishi U, Seki K, Yamaguchi U, Nakatani F, Kawai A, Chuman H, Beppu Y: Prognostic implications of glucose transporter protein-1 (glut-1) overexpression in bone and soft-tissue sarcomas. Jpn J Clin Oncol. 2007, 37: 955-960. 10.1093/jjco/hym125.CrossRefPubMed
13.
Kato H, Takita J, Miyazaki T, Nakajima M, Fukai Y, Masuda N, Fukuchi M, Manda R, Ojima H, Tsukada K, Kuwano H: Glut-1 glucose transporter expression in esophageal squamous cell carcinoma is associated with tumor aggressiveness. Anticancer Res. 2002, 22: 2635-2639.PubMed
14.
Legan M, Luzar B, Marolt VF: Expression of cyclooxygenase-2, glucose transporter-1 and angiogenesis in gallbladder carcinomas and their impact on prognosis. Scand J Gastroenterol. 2009, 44: 1101-1108. 10.1080/00365520903121685.CrossRefPubMed
15.
Pizzi S, Porzionato A, Pasquali C, Guidolin D, Sperti C, Fogar P, Macchi V, De Caro R, Pedrazzoli S, Parenti A: Glucose transporter-1 expression and prognostic significance in pancreatic carcinogenesis. Histol Histopathol. 2009, 24: 175-185.PubMed
16.
Stackhouse BL, Williams H, Berry P, Russell G, Thompson P, Winter JL, Kute T: Measurement of glut-1 expression using tissue microarrays to determine a race specific prognostic marker for breast cancer. Breast Cancer Res Treat. 2005, 93: 247-253. 10.1007/s10549-005-5158-y.CrossRefPubMed
17.
Tateishi U, Yamaguchi U, Seki K, Terauchi T, Arai Y, Hasegawa T: Glut-1 expression and enhanced glucose metabolism are associated with tumour grade in bone and soft tissue sarcomas: a prospective evaluation by [18F]fluorodeoxyglucose positron emission tomography. Eur J Nucl Med Mol Imaging. 2006, 33: 683-691. 10.1007/s00259-005-0044-8.CrossRefPubMed
18.
Eckert AW, Lautner MH, Taubert H, Schubert J, Bilkenroth U: Expression of glut-1 is a prognostic marker for oral squamous cell carcinoma patients. Oncol Rep. 2008, 20: 1381-1385.PubMed
19.
Oliver RJ, Woodwards RT, Sloan P, Thakker NS, Stratford IJ, Airley RE: Prognostic value of facilitative glucose transporter glut-1 in oral squamous cell carcinomas treated by surgical resection; results of EORTC translational research fund studies. Eur J Cancer. 2004, 40: 503-507. 10.1016/j.ejca.2003.10.024.CrossRefPubMed
20.
Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S: The reverse warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009, 8: 3984-4001. 10.4161/cc.8.23.10238.CrossRefPubMed
21.
Nguyen XC, So Y, Chung JH, Lee WW, Park SY, Kim SE: High correlations between primary tumours and loco-regional metastatic lymph nodes in non-small-cell lung cancer with respect to glucose transporter type 1-mediated 2-deoxy-2-F18-fluoro-D-glucose uptake. Eur J Cancer. 2008, 44: 692-698. 10.1016/j.ejca.2008.02.009.CrossRefPubMed
22.
Kobayashi M, Kaida H, Kawahara A, Hattori S, Kurata S, Hayakawa M, Hirose Y, Uchida M, Kage M, Fujita H: The relationship between GLUT-1 and vascular endothelial growth factor expression and 18F-FDG uptake in esophageal squamous cell cancer patients. Clin Nucl Med. 2012, 37: 447-452. 10.1097/RLU.0b013e31823924bb.CrossRefPubMed
23.
Abrams HL, Spiro R, Goldstein N: Metastases in carcinoma; analysis of 1000 autopsied cases. Cancer. 1950, 3: 74-85. 10.1002/1097-0142(1950)3:1<74::AID-CNCR2820030111>3.0.CO;2-7.CrossRefPubMed
24.
Gilbert H, Kagan A: Fundamental aspects of metastasis. 1976, Amsterdam: North-Holland Publishing; Weiss L
25.
Nystrom JS, Weiner JM, Heffelfinger-Juttner J, Irwin LE, Bateman JR, Wolf RM: Metastatic and histologic presentations in unknown primary cancer. Semin Oncol. 1977, 4: 53-58.PubMed
26.
Le Chevalier T, Cvitkovic E, Caille P, Harvey J, Contesso G, Spielmann M, Rouesse J: Early metastatic cancer of unknown primary origin at presentation: a clinical study of 302 consecutive autopsied patients. Arch Intern Med. 1988, 148: 2035-2039. 10.1001/archinte.1988.00380090101024.CrossRefPubMed
27.
Yamada T, Uchida M, Kwang-Lee K, Kitamura N, Yoshimura T, Sasabe E, Yamamoto T: Correlation of metabolism/hypoxia markers and fluorodeoxyglucose uptake in oral squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2012, 113: 464-471.CrossRef
28.
Kim S, Kim do H, Jung WH, Koo JS: Expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer. Endocr Relat Cancer. 2013, 20: 339-348. 10.1530/ERC-12-0398.CrossRefPubMed
29.
Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG: Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”: a transcriptional informatics analysis with validation. Cell Cycle. 2010, 9: 2201-2219. 10.4161/cc.9.11.11848.CrossRefPubMed
30.
Chang H, Shyu KG, Lee CC, Tsai SC, Wang BW, Hsien Lee Y, Lin S: GL331 inhibits HIF-1alpha expression in a lung cancer model. Biochem Biophys Res Commun. 2003, 302: 95-100. 10.1016/S0006-291X(03)00111-6.CrossRefPubMed
31.
Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW: YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst. 2003, 95: 516-525. 10.1093/jnci/95.7.516.CrossRefPubMed
32.
Mohanti BK, Rath GK, Anantha N, Kannan V, Das BS, Chandramouli BA, Banerjee AK, Das S, Jena A, Ravichandran R: Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys. 1996, 35: 103-111. 10.1016/S0360-3016(96)85017-6.CrossRefPubMed
33.
Aft RL, Zhang FW, Gius D: Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. Br J Cancer. 2002, 87: 805-812. 10.1038/sj.bjc.6600547.PubMedCentralCrossRefPubMed
34.
Vullo D, Franchi M, Gallori E, Pastorek J, Scozzafava A, Pastorekova S, Supuran CT: Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulfonamides. Bioorg Med Chem Lett. 2003, 13: 1005-1009. 10.1016/S0960-894X(03)00091-X.CrossRefPubMed
35.
Gallagher SM, Castorino JJ, Wang D, Philp NJ: Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res. 2007, 67: 4182-4189. 10.1158/0008-5472.CAN-06-3184.CrossRefPubMed
36.
Dova L, Pentheroudakis G, Golfinopoulos V, Malamou-Mitsi V, Georgiou I, Vartholomatos G, Ntemou A, Fountzilas G, Pavlidis N: Targeting c-KIT, PDGFR in cancer of unknown primary: a screening study for molecular markers of benefit. J Cancer Res Clin Oncol. 2008, 134: 697-704. 10.1007/s00432-007-0341-7.CrossRefPubMed
37.
Pavlidis N, Briassoulis E, Bai M, Fountzilas G, Agnantis N: Overexpression of C-myc, Ras and C-erbB-2 oncoproteins in carcinoma of unknown primary origin. Anticancer Res. 1995, 15: 2563-2567.PubMed
38.
Hainsworth JD, Lennington WJ, Greco FA: Overexpression of Her-2 in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. J Clin Oncol. 2000, 18: 632-635.PubMed
39.
van de Wouw AJ, Jansen RL, Griffioen AW, Hillen HF: Clinical and immunohistochemical analysis of patients with unknown primary tumour. A search for prognostic factors in UPT. Anticancer Res. 2004, 24: 297-301.PubMed
40.
Briasoulis E, Tsokos M, Fountzilas G, Bafaloukos D, Kosmidis P, Samantas E, Skarlos D, Nicolaides C, Pavlidis N: Bcl2 and p53 protein expression in metastatic carcinoma of unknown primary origin: biological and clinical implications. A Hellenic Co-operative Oncology Group study. Anticancer Res. 1998, 18: 1907-1914.PubMed
Metadata
Title
Metabolic phenotypes in primary unknown metastatic carcinoma
Authors
Hye Min Kim
Do Hee Kim
Woo Hee Jung
Ja Seung Koo
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2014
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-12-2

Other articles of this Issue 1/2014

Journal of Translational Medicine 1/2014 Go to the issue

Research

AMG 900, a potent inhibitor of aurora kinases causes pharmacodynamic changes in p-Histone H3 immunoreactivity in human tumor xenografts and proliferating mouse tissues

Research

Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients

Review

Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases

Research

Endometrial regenerative cells as a novel cell therapy attenuate experimental colitis in mice

Research

In vitro blood cell responsiveness to IFN-α predicts clinical response independently of IL28B in hepatitis C virus genotype 1 infected patients

Editorial

Single-cell transcriptomics: an emerging tool in the study of cardiometabolic disease
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits