Cancer Biomarkers, biotechnology reagents, antibodies and proteins

Finding The Right Biomarker for Cancer Research

Cancer has a major impact on society around the world and biomarkers play a pivotal role in cancer research. Leinco technologies brings you numerous resources for validating biomarkers against different cancer types and stages, discovering new biomarkers to improve diagnostics and drug development, identifying the impact biomarkers have on disease progression, and more. Take a look at the following list of cancer types and associated antibodies and proteins reported in applications.

 

Programmed Death-1 (PD-1) & Programmed Death-1 Ligand (PD-L1)

PD-L1 is a transmembrane protein that interacts with PD-1 to suppress lymphocyte activation and function, promote regulatory T cell responses, and impair anti-tumor T cell immune responses. PD-L1 is upregulated in non-small cell lung cancer (NSCLC) and correlates to the degree of tumor cell differentiation and metastasis1, suggesting its potential as a prognostic biomarker. PD-L1 is also a predictive biomarker, and IHC assays measure levels on lung cancer tissue to determine responsiveness to checkpoint inhibitors that target PD-1 or PD-L1. Tumor-infiltrating CD8+ T cells have increased PD-1 expression in patients with NSCLC, associated with impaired immune function2.

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  1. Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012 Nov;98(6):751-5. doi: 10.1700/1217.13499. PMID: 23389362.
  2. Zhang Y, Huang S, Gong D, Qin Y, Shen Q. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol Immunol. 2010 Sep;7(5):389-95. doi: 10.1038/cmi.2010.28. Epub 2010 May 31. PMID: 20514052; PMCID: PMC4002677.

Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4)

CTLA-4 is a checkpoint protein present on the surface of activated T cells that negatively regulates T cell proliferation and T cell-mediated immune responses. CTLA-4 is expressed in NSCLC but not normal bronchial tissues and has prognostic value1,2. CTLA-4 expression on tumor cells contributes to tumorigenesis by increasing PD-L1 expression and cancer cell proliferation via the EGFR pathway2. Although anti-CTLA-4 antibodies, such as ipilimumab, are not effective treatments for NSCLC on their own, combination treatment with PD-1/PD-L1 inhibitors shows promise in PD-L1 positive NSCLC patients3.

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  1. Salvi S, Fontana V, Boccardo S, Merlo DF, Margallo E, Laurent S, Morabito A, Rijavec E, Dal Bello MG, Mora M, Ratto GB, Grossi F, Truini M, Pistillo MP. Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer. Cancer Immunol Immunother. 2012 Sep;61(9):1463-72. doi: 10.1007/s00262-012-1211-y. Epub 2012 Feb 9. PMID: 22318401.
  2. Zhang H, Dutta P, Liu J, et al. Tumour cell-intrinsic CTLA4 regulates PD-L1 expression in non-small cell lung cancer. J Cell Mol Med. 2019;23(1):535-542. doi:10.1111/jcmm.13956
  3. Puri S, Shafique M. Combination checkpoint inhibitors for treatment of non-small-cell lung cancer: an update on dual anti-CTLA-4 and anti-PD-1/PD-L1 therapies. Drugs Context. 2020;9:2019-9-2. Published 2020 Jan 13. doi:10.7573/dic.2019-9-2

Vascular Endothelial Growth Factor (VEGF)

VEGF is a homodimeric glycoprotein that promotes angiogenesis in both physiological and pathological contexts, such as cancer1. VEGF contributes to lung cancer tumorigenesis through autocrine signaling, promoting epithelial-mesenchymal transition and invasiveness2. VEGF levels may be a useful diagnostic and prognostic biomarker for lung cancer, with relatively high sensitivity and specificity for NSCLC3.

View VEGF Products View Bevacizumab VEGF Biosimilars

  1. Ahluwalia A, Jones MK, Tarnawski AS. et al. Key role of endothelial importin-ɑ in VEGF expression and gastric angiogenesis: novel insight into aging gastropathy. Am J Physiol Gastrointest Liver Physiol. 2014;306:G338–45.
  2. Desai S, Laskar S, Pandey BN. Autocrine IL-8 and VEGF mediate epithelial-mesenchymal transition and invasiveness via p38/JNK-ATF-2 signalling in A549 lung cancer cells. Cell Signal. 2013 Sep;25(9):1780-91. doi: 10.1016/j.cellsig.2013.05.025. Epub 2013 May 25. PMID: 23714383.
  3. Lai Y, Wang X, Zeng T, Xing S, Dai S, Wang J, Chen S, Li X, Xie Y, Zhu Y, Liu W. Serum VEGF levels in the early diagnosis and severity assessment of non-small cell lung cancer. J Cancer. 2018 Apr 6;9(9):1538-1547. doi: 10.7150/jca.23973. PMID: 29760791; PMCID: PMC5950582.

Epidermal Growth Factor Receptor (EGFR)

EGFR is a transmembrane glycoprotein belonging to the tyrosine kinase family and plays essential roles in cell proliferation, survival, differentiation, and migration. Mutations in EGFR are frequently detected in a subset of lung cancer patients and are associated with increased VEGF expression1. Mutations in EGFR are a predictive biomarker of treatment response to EGFR inhibitors2.

View EGFR Products View Cetuximab EGFR Biosimilars

  1. Reinmuth N, Jauch A, Xu EC, Muley T, Granzow M, Hoffmann H, Dienemann H, Herpel E, Schnabel PA, Herth FJ, Gottschling S, Lahm H, Steins M, Thomas M, Meister M. Correlation of EGFR mutations with chromosomal alterations and expression of EGFR, ErbB3 and VEGF in tumor samples of lung adenocarcinoma patients. Lung Cancer. 2008 Nov;62(2):193-201. doi: 10.1016/j.lungcan.2008.03.011. Epub 2008 May 1. PMID: 18450321.
  2. Vincent MD, Kuruvilla MS, Leighl NB, Kamel-Reid S. Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS. Curr Oncol. 2012;19(Suppl 1):S33-S44. doi:10.3747/co.19.1149

FAS/CD95

Fas is a death receptor that induces apoptosis upon binding to Fas ligand (FasL) on cytotoxic T cells. Fas expression is decreased in lung tumor tissues, contributing to tumorigenesis by evading the immune system and apoptosis1. In contrast, FasL is overexpressed in small cell lung carcinoma and correlates with advanced tumor stage, and may promote paracrine killing of cytotoxic T cells in the absence of Fas expression on tumor cells1.

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  1. Viard-Leveugle I, Veyrenc S, French LE, Brambilla C, Brambilla E. Frequent loss of Fas expression and function in human lung tumours with overexpression of FasL in small cell lung carcinoma. J Pathol. 2003 Oct;201(2):268-77. doi: 10.1002/path.1428. PMID: 14517844.

Other Lung Cancer Biomarkers

Programmed Death-ligand 1 (PD-L1)

PD-L1 is a transmembrane protein that interacts with PD-1 to suppress lymphocyte activation and function, promote regulatory T cell responses, and impair anti-tumor T cell immune responses. In metastatic ovarian cancer tissues, a higher percentage of metastatic tumors express PD-L1 compared to the primary tumor, which is associated with poor prognostic factors, including high proliferation and histologic grade1. PD-L1 expression is also determined by IHC to select patients for treatments targeting the PD-1/PD-L1 pathway.

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  1. Parvathareddy SK, Siraj AK, Al-Badawi IA, Tulbah A, Al-Dayel F, Al-Kuraya KS. Differential expression of PD-L1 between primary and metastatic epithelial ovarian cancer and its clinico-pathological correlation. Sci Rep. 2021 Feb 12;11(1):3750. doi: 10.1038/s41598-021-83276-z. PMID: 33580098; PMCID: PMC7881132.

Programmed Death-ligand 2 (PD-L2)

PD-L2 is a second ligand to PD-1 and is upregulated on dendritic cells, macrophages, and endothelial cells during inflammation and contributes to T cell exhaustion. PD-L2 expression is elevated in ovarian cancer tissue compared to non-malignant tissue1. In addition, high expression of PD-L2 is an independent prognostic factor for overall survival in ovarian cancer patients2.

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  1. Miao YR, Thakkar KN, Qian J, Kariolis MS, Wei H, Nandagopal S, et al. Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer. bioRxiv 2020.01.19.911941; doi: https://doi.org/10.1101/2020.01.19.911941
  2. Piao J, Lim HJ, Lee M. Prognostic value of programmed cell death ligand-1 expression in ovarian cancer: an updated meta-analysis. Obstet Gynecol Sci. 2020;63(3):346-356. doi:10.5468/ogs.2020.63.3.346

Human Epidermal Growth Factor Receptor 2 (HER-2)/ErbB2

HER-2 is a tyrosine kinase receptor that plays an important role in cell proliferation and tumor metastasis1. HER-2 is overexpressed in 6-30% of patients with ovarian cancer and is associated with progression and poor prognosis2,3.

View Trastuzumab HER-2/ErbB2 Biosimilars

  1. Cai Y, Wang J, Zhang L, Wu D, Yu D, Tian X, Liu J, Jiang X, Shen Y, Zhang L, Ren M, Huang P. Expressions of fatty acid synthase and HER2 are correlated with poor prognosis of ovarian cancer. Med Oncol. 2015 Jan;32(1):391. doi: 10.1007/s12032-014-0391-z. Epub 2014 Nov 30. PMID: 25433947; PMCID: PMC4247847. 
  2. Luo H, Xu X, Ye M, Sheng B, Zhu X. The prognostic value of HER2 in ovarian cancer: A meta-analysis of observational studies. PLoS One. 2018;13(1):e0191972. Published 2018 Jan 30. doi:10.1371/journal.pone.0191972
  3. Bonello M, Sims AH, Langdon SP. Human epidermal growth factor receptor targeted inhibitors for the treatment of ovarian cancer. Cancer Biol Med. 2018;15(4):375-388. doi:10.20892/j.issn.2095-3941.2018.0062

Insulin-like Growth Factor-binding Protein 2 (IGFBP-2)

IGFBP-2 belongs to the IGFBP family and regulates the function of IGF, contributing to cell proliferation, invasion, angiogenesis, and apoptosis. IGFBP-2 is expressed at high levels in high-grade ovarian serous carcinoma1 and enhances cancer cell invasion2. In addition, overexpression of IGFBP2 correlates with poor prognosis and overall survival in chemotherapy-treated patients3.

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  1. Wang H, Rosen DG, Wang H, Fuller GN, Zhang W, Liu J. Insulin-like growth factor-binding protein 2 and 5 are differentially regulated in ovarian cancer of different histologic types. Mod Pathol. 2006 Sep;19(9):1149-56. doi: 10.1038/modpathol.3800637. Epub 2006 May 26. PMID: 16729015.
  2. Lee EJ, Mircean C, Shmulevich I, Wang H, Liu J, Niemistö A, Kavanagh JJ, Lee JH, Zhang W. Insulin-like growth factor binding protein 2 promotes ovarian cancer cell invasion. Mol Cancer. 2005 Feb 2;4(1):7. doi: 10.1186/1476-4598-4-7. PMID: 15686601; PMCID: PMC549074.
  3. Wang J, Luo XX, Tang YL, Xu JX, Zeng ZG. The prognostic values of insulin-like growth factor binding protein in breast cancer. Medicine (Baltimore). 2019;98(19):e15561. doi:10.1097/MD.0000000000015561

Human Epidermal Growth Factor Receptor 2 (HER-2)/ErbB2

HER-2 is a tyrosine kinase receptor that plays an important role in cell proliferation and tumor metastasis1. HER2 is overexpressed in approximately 20% of breast cancer tumors and is associated with aggressive disease, tumor relapse, and lower survival2. HER2 overexpression can predict response to therapy, such as to the anti-HER2 monoclonal antibody trastuzumab3; therefore, HER2 expression is measured in all patients with invasive breast cancer to determine treatment decisions, most commonly using IHC.

View Trastuzumab HER-2/ErbB2 Biosimilars

  1. Cai Y, Wang J, Zhang L, Wu D, Yu D, Tian X, Liu J, Jiang X, Shen Y, Zhang L, Ren M, Huang P. Expressions of fatty acid synthase and HER2 are correlated with poor prognosis of ovarian cancer. Med Oncol. 2015 Jan;32(1):391. doi: 10.1007/s12032-014-0391-z. Epub 2014 Nov 30. PMID: 25433947; PMCID: PMC4247847. 
  2. Saba NF, Yom SS, Haigentz M, El-Rayes B. Monoclonal Antibodies against Epidermal Growth Factor Receptor in Solid Tumors. Chemother Res Pract. 2012;2012:291421. doi: 10.1155/2012/291421. Epub 2012 Dec 24. PMID: 23320170; PMCID: PMC3540736.
  3. Wang J, Xu B. Targeted therapeutic options and future perspectives for HER2-positive breast cancer. Signal Transduct Target Ther. 2019 Sep 13;4:34. doi: 10.1038/s41392-019-0069-2. PMID: 31637013; PMCID: PMC6799843.

Epidermal Growth Factor Receptor (EGFR)

EGFR is a transmembrane glycoprotein belonging to the tyrosine kinase family and plays essential roles in cell proliferation, survival, differentiation, and migration. EGFR is overexpressed in approximately 50% of patients with triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC)1. Enhanced EGFR expression is also associated with metastasis and mortality in TNBC patients2.

View EGFR Products View Cetuximab EGFR Biosimilars

  1. Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat. 2012 Nov;136(2):331-45. doi: 10.1007/s10549-012-2289-9. Epub 2012 Oct 17. PMID: 23073759; PMCID: PMC3832208.

p53

p53 regulates cell cycle progression, DNA repair, and apoptosis and plays an essential role in tumor suppression following DNA damage1. The p53 gene is mutated in 80% of triple-negative breast cancer (TNBC), in which it contributes to cancer progression2. Therefore, p53 is a useful diagnostic biomarker for TNBC, the most lethal breast cancer with limited therapeutic options. p53 expression is also associated with poor survival in patients with TNBC3.

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  1. Reinhardt HC, Schumacher B. The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet. 2012;28(3):128-136. doi:10.1016/j.tig.2011.12.002
  2. Network TCGA. Comprehensive molecular portraits of human breast tumors. Nature 2012;490:61–70.
  3. Li JP, Zhang XM, Zhang Z, Zheng LH, Jindal S, Liu YJ. Association of p53 expression with poor prognosis in patients with triple-negative breast invasive ductal carcinoma. Medicine (Baltimore). 2019 May;98(18):e15449. doi: 10.1097/MD.0000000000015449. PMID: 31045815; PMCID: PMC6504250.
  4. Ali R, Wendt MK. The paradoxical functions of EGFR during breast cancer progression. Signal Transduct Target Ther. 2017;2:16042–. doi: 10.1038/sigtrans.2016.42. Epub 2017 Jan 20. PMID: 28435746; PMCID: PMC5397119.

Other Breast Cancer Biomarkers

Vascular Endothelial Growth Factor (VEGF)

VEGF is a homodimeric glycoprotein that promotes angiogenesis in both physiological and pathological contexts, such as colorectal cancer1,2. VEGF and its receptors are overexpressed in colorectal cancer, with higher circulating VEGF levels in metastatic tumors than non-metastatic tumors, indicating its potential as a diagnostic and prognostic biomarker3.

View VEGF Products View Bevacizumab VEGF Biosimilars

  1. Ahluwalia A, Jones MK, Tarnawski AS. et al. Key role of endothelial importin-ɑ in VEGF expression and gastric angiogenesis: novel insight into aging gastropathy. Am J Physiol Gastrointest Liver Physiol. 2014;306:G338–45.
  2. Ellis LM. A targeted approach for antiangiogenic therapy of metastatic human colon cancer. Am Surg. 2003 Jan;69(1):3-10. PMID: 12575772.
  3. De Vita F, Orditura M, Lieto E, Infusino S, Morgillo F, Martinelli E, Castellano P, Romano C, Ciardiello F, Catalano G, Pignatelli C, Galizia G. Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma. Cancer. 2004 Jan 15;100(2):270-8. doi: 10.1002/cncr.11911. PMID: 14716760

Epidermal Growth Factor Receptor (EGFR)

EGFR is a transmembrane glycoprotein belonging to the tyrosine kinase family and plays essential roles in cell proliferation, survival, differentiation, and migration. EGFR contributes to colorectal cancer initiation and progression, and monoclonal antibodies targeting EGFR are approved treatment strategies for metastatic colorectal cancer1. EGFR is overexpressed in 80% of patients with colorectal cancer and is associated with tumor stage2, demonstrating potential diagnostic and prognostic potential. The number of EGFR copies may also predict treatment response to anti-EGFR monoclonal antibodies3.

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  1. Markman B, Javier Ramos F, Capdevila J, Tabernero J. EGFR and KRAS in colorectal cancer. Adv Clin Chem. 2010;51:71-119. doi: 10.1016/s0065-2423(10)51004-7. PMID: 20857619.
  2. Spano JP, Lagorce C, Atlan D, Milano G, Domont J, Benamouzig R, Attar A, Benichou J, Martin A, Morere JF, Raphael M, Penault-Llorca F, Breau JL, Fagard R, Khayat D, Wind P. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol. 2005 Jan;16(1):102-8. doi: 10.1093/annonc/mdi006. PMID: 15598946.
  3. Shen WD, Chen HL, Liu PF. EGFR gene copy number as a predictive biomarker for resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer treatment: a meta-analysis. Chin J Cancer Res. 2014;26(1):59-71. doi:10.3978/j.issn.1000-9604.2014.01.10

Insulin-like Growth Factor-binding Protein 2 (IGFBP-2) 

IGFBP-2 belongs to the IGFBP family and regulates the function of IGF, contributing to cell proliferation, invasion, angiogenesis, and apoptosis.  IGFBP-2 serum levels are elevated in patients with colorectal cancer compared to healthy controls and are associated with an increased risk of mortality and metastasis1,2.

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  1. Vocka M, Langer D, Fryba V, et al. Novel serum markers HSP60, CHI3L1, and IGFBP-2 in metastatic colorectal cancer. Oncol Lett. 2019;18(6):6284-6292. doi:10.3892/ol.2019.10925
  2. Liou JM, Shun CT, Liang JT, Chiu HM, Chen MJ, Chen CC, Wang HP, Wu MS, Lin JT. Plasma insulin-like growth factor-binding protein-2 levels as diagnostic and prognostic biomarker of colorectal cancer. J Clin Endocrinol Metab. 2010 Apr;95(4):1717-25. doi: 10.1210/jc.2009-2668. Epub 2010 Feb 15. PMID: 20157191.

Other Colorectal Cancer Biomarkers

Vascular Endothelial Growth Factor (VEGF)

VEGF is a homodimeric glycoprotein that promotes angiogenesis in both physiological and pathological contexts, such as cancer1. VEGF contributes to bladder cancer cell growth and proliferation2,3. Elevated VEGF expression is observed in bladder cancer cells4, and increased tumor, serum, and urine levels are associated with disease recurrence, progression, and poor prognosis5,6.

View VEGF Products View Bevacizumab VEGF Biosimilars

  1. Ahluwalia A, Jones MK, Tarnawski AS. et al. Key role of endothelial importin-ɑ in VEGF expression and gastric angiogenesis: novel insight into aging gastropathy. Am J Physiol Gastrointest Liver Physiol. 2014;306:G338–45.
  2. García-Closas M, Malats N, Real FX, Yeager M, Welch R, Silverman D, Kogevinas M, Dosemeci M, Figueroa J, Chatterjee N, Tardón A, Serra C, Carrato A, García-Closas R, Murta-Nascimento C, Rothman N, Chanock SJ. Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. PLoS Genet. 2007 Feb 23;3(2):e29. doi: 10.1371/journal.pgen.0030029. Epub 2007 Jan 4. PMID: 17319747; PMCID: PMC1802828.
  3. Kunze D, Wuttig D, Kausch I, Blietz C, Blumhoff L, Burmeister Y, Kraemer K, Fuessel S, Toma M, Schwenzer B, Meye A, Grimm MO, Hakenberg OW, Jocham D, Wirth MP. Antisense-mediated inhibition of survivin, hTERT and VEGF in bladder cancer cells in vitro and in vivo. Int J Oncol. 2008 May;32(5):1049-56. PMID: 18425331.
  4. Urquidi V, Goodison S, Kim J, Chang M, Dai Y, Rosser CJ. Vascular endothelial growth factor, carbonic anhydrase 9, and angiogenin as urinary biomarkers for bladder cancer detection. Urology. 2012;79(5):1185.e1-1185.e11856. doi:10.1016/j.urology.2012.01.016
  5. Narayanan S, Srinivas S. Incorporating VEGF-targeted therapy in advanced urothelial cancer. Ther Adv Med Oncol. 2017;9(1):33-45. doi:10.1177/1758834016667179
  6. Verma A, Degrado J, Hittelman AB, Wheeler MA, Kaimakliotis HZ, Weiss RM. Effect of mitomycin C on concentrations of vascular endothelial growth factor and its receptors in bladder cancer cells and in bladders of rats intravesically instilled with mitomycin C. BJU Int. 2011 Apr;107(7):1154-61. doi: 10.1111/j.1464-410X.2010.09543.x. Epub 2010 Aug 24. PMID: 20735383.

Survivin/BIRC5

Survivin is an inhibitor of apoptosis protein family member and suppresses apoptosis by binding to caspases-3, -7, and -91. Survivin is detected in the urine and tumor tissue of patients with bladder cancer but absent in normal bladder tissues, making it a sensitive diagnostic biomarker2-3. Survivin also has prognostic potential in bladder cancer, as its expression is associated with disease recurrence and mortality4.

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  1. Jaiswal PK, Goel A, Mittal RD. Survivin: A molecular biomarker in cancer. Indian J Med Res. 2015;141(4):389-397. doi:10.4103/0971-5916.159250
  2. Shariat SF, Casella R, Khoddami SM, Hernandez G, Sulser T, Gasser TC, Lerner SP. Urine detection of survivin is a sensitive marker for the noninvasive diagnosis of bladder cancer. J Urol. 2004 Feb;171(2 Pt 1):626-30. doi: 10.1097/01.ju.0000107826.78479.90. PMID: 14713774.
  3. Swana HS, Grossman D, Anthony JN, Weiss RM, Altieri DC. Tumor content of the antiapoptosis molecule survivin and recurrence of bladder cancer. N Engl J Med. 1999 Aug 5;341(6):452-3. doi: 10.1056/NEJM199908053410614. PMID: 10438269.
  4. Shariat SF, Ashfaq R, Karakiewicz PI, Saeedi O, Sagalowsky AI, Lotan Y. Survivin expression is associated with bladder cancer presence, stage, progression, and mortality. Cancer. 2007 Mar 15;109(6):1106-13. doi: 10.1002/cncr.22521. PMID: 17311310.

CCL18

CCL18 is a C-C chemokine involved in the chemotaxis of both inflammatory and regulatory immune cells. CCL18 is a potential diagnostic biomarker for bladder cancer as increased expression of CCL18 is found in the urine of patients with bladder cancer1,2.  In addition, CCL18 may promote the migration, invasion, and epithelial-mesenchymal transition of bladder cancer cells, and overexpression of CLC18 in bladder cancer tissues is associated with tumor stage and poor prognosis3.

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  1. Urquidi V, Kim J, Chang M, Dai Y, Rosser CJ, Goodison S. CCL18 in a multiplex urine-based assay for the detection of bladder cancer. PLoS One. 2012;7(5):e37797. doi:10.1371/journal.pone.0037797
  2. Miyake M, Ross S, Lawton A, et al. Investigation of CCL18 and A1AT as potential urinary biomarkers for bladder cancer detection. BMC Urol. 2013;13:42. Published 2013 Sep 5. doi:10.1186/1471-2490-13-42
  3. Liu X, Xu X, Deng W, et al. CCL18 enhances migration, invasion and EMT by binding CCR8 in bladder cancer cells. Mol Med Rep. 2019;19(3):1678-1686. doi:10.3892/mmr.2018.9791

Other Bladder Cancer Biomarkers

CTLA-4

CTLA-4 is a checkpoint protein present on activated T cells that negatively regulates T cell proliferation and T cell-mediated immune responses. CTLA4 is overexpressed on chronic lymphocytic leukemia (CLL) cells compared to B cells from healthy controls1. In addition, higher expression of CTLA-4 in CLL cells correlates with better clinical outcomes and lower leukocyte and lymphocyte counts2,3, possibly due to the role of CTLA-4 in inhibiting the proliferation and survival of CLL cells4.

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  1. Kosmaczewska A, Ciszak L, Suwalska K, Wolowiec D, Frydecka I. CTLA-4 overexpression in CD19+/CD5+ cells correlates with the level of cell cycle regulators and disease progression in B-CLL patients. Leukemia. 2005 Feb;19(2):301-4. doi: 10.1038/sj.leu.2403588. PMID: 15549146. 
  2. Joshi AD, Hegde GV, Dickinson JD, Mittal AK, Lynch JC, Eudy JD, Armitage JO, Bierman PJ, Bociek RG, Devetten MP, Vose JM, Joshi SS. ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressing B-cell chronic lymphocytic leukemia. Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5295-304. doi: 10.1158/1078-0432.CCR-07-0283. PMID: 17875758.
  3. Ciszak L, Frydecka I, Wolowiec D, Szteblich A, Kosmaczewska A. CTLA-4 affects expression of key cell cycle regulators of G0/G1 phase in neoplastic lymphocytes from patients with chronic lymphocytic leukaemia. Clin Exp Med. 2016 Aug;16(3):317-32. doi: 10.1007/s10238-015-0360-7. Epub 2015 May 24. PMID: 26003188; PMCID: PMC4969362.
  4. Mittal AK, Chaturvedi NK, Rohlfsen RA, Gupta P, Joshi AD, Hegde GV, Bociek RG, Joshi SS. Role of CTLA4 in the proliferation and survival of chronic lymphocytic leukemia. PLoS One. 2013 Aug 1;8(8):e70352. doi: 10.1371/journal.pone.0070352. PMID: 23936412; PMCID: PMC3731360.

CD52

CD52 is a GPI-anchored glycoprotein that is expressed on hematopoietic cells, with highest expression on lymphocytes and neoplastic B cells1. Soluble CD52 is released from CLL cells and detected at high levels in the plasma of CLL patients, which is correlated with cancer stage2. High soluble CD52 levels predict progression following treatment with fludarabine, cyclophosphamide, and rituximab3. Similarly, high CD52 mRNA levels are associated with shorter survival following treatment with the anti-CD52 anbitody alemtuzumab4.

View CD52 Alemtuzumab Biosimilars

  1. Klabusay M, Sukova V, Coupek P, Brychtova Y, Mayer J. Different levels of CD52 antigen expression evaluated by quantitative fluorescence cytometry are detected on B-lymphocytes, CD 34+ cells and tumor cells of patients with chronic B-cell lymphoproliferative diseases. Cytometry B Clin Cytom. 2007 Sep;72(5):363-70. doi: 10.1002/cyto.b.20181. PMID: 17428002. 
  2. Albitar M, Do KA, Johnson MM, Giles FJ, Jilani I, O’Brien S, Cortes J, Thomas D, Rassenti LZ, Kipps TJ, Kantarjian HM, Keating M. Free circulating soluble CD52 as a tumor marker in chronic lymphocytic leukemia and its implication in therapy with anti-CD52 antibodies. Cancer. 2004 Sep 1;101(5):999-1008. doi: 10.1002/cncr.20477. PMID: 15329909.
  3. Alatrash G, Albitar M, O’Brien S, Wang X, Manshouri T, Faderl S, Ferrajoli A, Burger J, Garcia-Manero G, Kantarjian HM, Lerner S, Keating MJ, Wierda WG. Circulating CD52 and CD20 levels at end of treatment predict for progression and survival in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab (FCR). Br J Haematol. 2010 Feb;148(3):386-93. doi: 10.1111/j.1365-2141.2009.07965.x. Epub 2009 Nov 6. PMID: 19895616; PMCID: PMC4476391.
  4. Alatrash G, Albitar M, O’Brien S, et al. Circulating CD52 and CD20 levels at end of treatment predict for progression and survival in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab (FCR). Br J Haematol. 2010;148(3):386-393. doi:10.1111/j.1365-2141.2009.07965.x

Interleukin 6 (IL-6)

Renal cell carcinoma cells secrete IL-6, an autocrine tumor growth factor that activates the JAK-STAT pathway1. Therefore, an increase in serum IL-6 levels is an independent prognostic factor for survival metastatic RCC patients2. IL-6 may also predict response to treatment with the tyrosine kinase inhibitor pazopanib3.

View IL-6 Products View Sarilumab IL-6 Biosimilars

  1. Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014 Nov;70(1):11-20. doi: 10.1016/j.cyto.2014.05.024. Epub 2014 Jun 28. PMID: 24986424.
  2. Negrier S, Perol D, Menetrier-Caux C, Escudier B, Pallardy M, Ravaud A, Douillard JY, Chevreau C, Lasset C, Blay JY; Groupe Francais d’Immunotherapie. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6–from the Groupe Francais d’Immunotherapie. J Clin Oncol. 2004 Jun 15;22(12):2371-8. doi: 10.1200/JCO.2004.06.121. Erratum in: J Clin Oncol. 2004 Nov 15;22(22):4656. Pallardy, Michel [corrected to Pallardy, Marc]. PMID: 15197198.
  3. Farber NJ, Kim CJ, Modi PK, Hon JD, Sadimin ET, Singer EA. Renal cell carcinoma: the search for a reliable biomarker. Transl Cancer Res. 2017;6(3):620-632. doi:10.21037/tcr.2017.05.19

Vascular Endothelial Growth Factor (VEGF)

VEGF is a homodimeric glycoprotein that promotes angiogenesis in both physiological and pathological contexts, such as cancer1. Approximately 60% of clear cell renal cell carcinomas are associated with loss of function of the VHL gene, which induces hypoxia-inducible factors and enhanced transcription and expression of VEGF, promoting angiogenesis2. Higher VEGF levels are associated with worse prognosis3 and may predict response to VEGF pathway inhibitors, such as sorafenib4.

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  1. Ahluwalia A, Jones MK, Tarnawski AS. et al. Key role of endothelial importin-ɑ in VEGF expression and gastric angiogenesis: novel insight into aging gastropathy. Am J Physiol Gastrointest Liver Physiol. 2014;306:G338–45.
  2. Rini BI. Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions. Clin Cancer Res. 2007 Feb 15;13(4):1098-106. doi: 10.1158/1078-0432.CCR-06-1989. PMID: 17317817.
  3. Jacobsen J, Rasmuson T, Grankvist K, Ljungberg B. Vascular endothelial growth factor as prognostic factor in renal cell carcinoma. J Urol. 2000 Jan;163(1):343-7. PMID: 10604387.
  4. Zurita AJ, Jonasch E, Wang X, et al. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2012;23(1):46-52. doi:10.1093/annonc/mdr047

Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

TRAIL is a cytokine that preferentially induces extrinsic apoptosis in cancer cells by binding to death receptors1. Serum levels of TRAIL are lower in renal cell carcinoma patients compared to healthy controls, identifying it as a potential diagnostic biomarker2. In addition, TRAIL may have prognostic value as serum TRAIL levels are lower in patients with metastasis and higher cancer stage2.

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  1. Wiley SR, Schooley K, Smolak PJ, et al: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 3:673–682. 1995.
  2. Toiyama D, Takaha N, Shinnoh M, Ueda T, Kimura Y, Nakamura T, Hongo F, Mikami K, Kamoi K, Kawauchi A, Miki T. Significance of serum tumor necrosis factor-related apoptosis-inducing ligand as a prognostic biomarker for renal cell carcinoma. Mol Clin Oncol. 2013 Jan;1(1):69-74. doi: 10.3892/mco.2012.35. Epub 2012 Oct 15. PMID: 24649125; PMCID: PMC3956254.

Epidermal Growth Factor Receptor (EGFR)

EGFR is a transmembrane glycoprotein belonging to the tyrosine kinase family and plays essential roles in cell proliferation, survival, differentiation, and migration. Overexpression of EGFR and mutations in its downstream mediators, such as Ras, are present in most pancreatic tumors1,2. EGFR overexpression is associated with higher mortality rates, extensive tumor growth, and metastasis3.

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  1. Grapa CM, Mocan T, Gonciar D, et al. Epidermal Growth Factor Receptor and Its Role in Pancreatic Cancer Treatment Mediated by Nanoparticles. Int J Nanomedicine. 2019;14:9693-9706. Published 2019 Dec 9. doi:10.2147/IJN.S226628
  2. Nedaeinia R, Avan A, Manian M, Salehi R, Ghayour-Mobarhan M. EGFR as a potential target for the treatment of pancreatic cancer: dilemma and controversies. Curr Drug Targets. 2014;15(14):1293–1301. doi:10.2174/1389450115666141125123003
  3. Yamanaka Y, Friess H, Kobrin MS, Buchler M, Beger HG, Korc M. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res. 1993;13(3):565–569.

IgG4

IgG4 is the least common IgG antibody, typically accounting for 4% of serum IgG. However, elevated IgG4 serum levels are found in some patients with pancreatic cancer1. In addition, high infiltration of IgG4-positive plasma cells may be an independent predictor of poor overall survival in pancreatic cancer patients after curative resection2.

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  1. Ngwa T, Law R, Hart P, Smyrk TC, Chari ST. Serum IgG4 elevation in pancreatic cancer: diagnostic and prognostic significance and association with autoimmune pancreatitis. Pancreas. 2015 May;44(4):557-60. doi: 10.1097/MPA.0000000000000297. PMID: 25785724.
  2. Liu Q, Niu Z, Li Y, Wang M, Pan B, Lu Z, Liao Q, Zhao Y. Immunoglobulin G4 (IgG4)-positive plasma cell infiltration is associated with the clinicopathologic traits and prognosis of pancreatic cancer after curative resection. Cancer Immunol Immunother. 2016 Aug;65(8):931-40. doi: 10.1007/s00262-016-1853-2. Epub 2016 Jun 6. PMID: 27271551.

Osteopontin (OPN)

The extracellular matrix protein, OPN, is a signaling molecule with various functions, including cell adhesion and migration, inflammation, and apoptosis. OPN is thought to promote tumorigenesis and metastasis and increases the invasiveness of pancreatic cancer cells1. OPN is overexpressed in pancreatic cancer and has similar sensitivity and specificity as the standard biomarker assay for diagnosing pancreatic cancer2.

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  1. Kolb A, Kleeff J, Guweidhi A, Esposito I, Giese NA, Adwan H, Giese T, Büchler MW, Berger MR, Friess H. Osteopontin influences the invasiveness of pancreatic cancer cells and is increased in neoplastic and inflammatory conditions. Cancer Biol Ther. 2005 Jul;4(7):740-6. doi: 10.4161/cbt.4.7.1821. Epub 2005 Jul 5. PMID: 15970685.
  2. Koopmann J, Fedarko NS, Jain A, Maitra A, Iacobuzio-Donahue C, Rahman A, Hruban RH, Yeo CJ, Goggins M. Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2004 Mar;13(3):487-91. PMID: 15006928.

GDF-15/MIC-1

GDF-15 is a transforming growth factor β superfamily cytokine that inhibits macrophage activation1. GDF-15 serum levels are elevated in pancreatic cancer patients compared with healthy controls2, and serum GDF-15 levels have similar diagnostic accuracy as the standard assay for pancreatic cancer4. Elevated expression of MIC-1 is associated with an androgen-independent phenotype and poor outcomes for patients with pancreatic cancer3. Poorer outcomes may arise from the role of MIC-1 in cancer cell metastasis or proliferation4,5.

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  1. Bootcov MR, Bauskin AR, Valenzuela SM, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A. 1997;94(21):11514-11519. doi:10.1073/pnas.94.21.11514
  2. Karan D, Kelly DL, Rizzino A, Lin MF, Batra SK . (2002). Expression profile of differentially-regulated genes during progression of androgen-independent growth in human prostate cancer cells. Carcinogenesis 23: 967–975.
  3. Chen SJ, Karan D, Johansson SL, Lin FF, Zeckser J, Singh AP et al. (2007). Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells. Prostate 67: 557–571.
  4. Chen SJ, Karan D, Johansson SL, Lin FF, Zeckser J, Singh AP et al. (2007). Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells. Prostate 67: 557–571.
  5. Senapati S, Rachagani S, Chaudhary K, Johansson SL, Singh RK, Batra SK. Overexpression of macrophage inhibitory cytokine-1 induces metastasis of human prostate cancer cells through the FAK-RhoA signaling pathway. Oncogene. 2010 Mar 4;29(9):1293-302. doi: 10.1038/onc.2009.420. Epub 2009 Nov 30. PMID: 19946339; PMCID: PMC2896817.

Other Pancreatic Cancer Biomarkers

CD47/HNK-1

CD47 is a ubiquitously expressed surface protein that binds to the ligand SIRPα on macrophages, inhibiting phagocytosis of self cells1,2. Therefore, cancer cells can evade phagocyte-mediated immunity by upregulating CD47. Tumor cell expression of CD47 varies between different types of sarcoma, with high expression in chordoma and angiosarcoma1.

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  1. Dancsok AR, Gao D, Lee AF, et al. Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas. Oncoimmunology. 2020;9(1):1747340. Published 2020 Apr 12.

Survivin/BIRC5

Survivin is an inhibitor of apoptosis protein family member and suppresses apoptosis by binding to caspases-3, -7, and -91. Survivin is expressed in osteosarcoma tumors, with minimal expression in normal tissues, making it a promising diagnostic marker2. Survivin also has prognostic potential, as patients with metastatic osteosarcoma exhibit higher survivin levels at initial biopsy, and levels are higher in patients with metastases than those without3,4.

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  1. Jaiswal PK, Goel A, Mittal RD. Survivin: A molecular biomarker in cancer. Indian J Med Res. 2015;141(4):389-397. doi:10.4103/0971-5916.159250
  2. Kong C, Hansen MF. Biomarkers in Osteosarcoma. Expert Opin Med Diagn. 2009;3(1):13-23. doi:10.1517/17530050802608496
  3. Osaka E, Suzuki T, Osaka S, Yoshida Y, Sugita H, Asami S, et al. Survivin as a prognostic factor for osteosarcoma patients. Acta Histochem Cytochem. 2006 Jul 1;39(3):95–100.
  4. Osaka E, Suzuki T, Osaka S, Yoshida Y, Sugita H, Asami S, et al. Survivin expression levels as independent predictors of survival for osteosarcoma patients. J Orthop Res. 2007 Jan;25(1):116–121.

Matrix Metalloproteinases (MMPs)

MMPs degrade collagen of the extracellular matrix, contributing to tissue remodeling as well as tumor invasion and metastasis. Expression of MMPs, including MMP-9 and MMP-1, correlates with metastasis and poor prognosis in osteosarcoma. Consistent with the role of MMPs in metastasis, in vitro treatment with MMP inhibitors inhibits osteosarcoma tumor cell invasion1-4.

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  1. Himelstein BP, Asada N, Carlton MR, Collins MH. Matrix metalloproteinase-9 (MMP-9) expression in childhood osseous osteosarcoma. Med Pediatr Oncol. 1998 Dec;31(6):471–474.
  2. Ferrari C, Benassi S, Ponticelli F, Gamberi G, Ragazzini P, Pazzaglia L, et al. Role of MMP-9 and its tissue inhibitor TIMP-1 in human osteosarcoma: findings in 42 patients followed for 1–16 years. Acta Orthop Scand. 2004 Aug;75(4):487–491. 
  3. Uchibori M, Nishida Y, Nagasaka T, Yamada Y, Nakanishi K, Ishiguro N. Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma. Int J Oncol. 2006 Jan;28(1):33–42.
  4. Bjørnland K, Flatmark K, Pettersen S, Aaasen AO, Fodstad O, Maelandsmo GM. Matrix metalloproteinases participate in osteosarcoma invasion. J Surg Res. 2005 Aug;127(2):151-6. doi: 10.1016/j.jss.2004.12.016. Epub 2005 Apr 14. PMID: 16083752.

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Galectin-3 (Gal-3)

Gal-3 binds to β-galactosidase on cell surface glycoproteins and regulates cell proliferation and apoptosis of normal and cancer cells. Gal-3 is strongly expressed by thyroid cancer tissues but not normal thyroid tissues and is reported in 90-100% of papillary thyroid carcinoma cases (PTC)1. Furthermore, Gal-3 expression correlates with tumor invasiveness and metastasis1; however, the prognostic abilities of Gal-3 are controversial and need further investigation.

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  1. Chiu CG, Strugnell SS, Griffith OL, et al. Diagnostic utility of galectin-3 in thyroid cancer. Am J Pathol. 2010;176(5):2067-2081. doi:10.2353/ajpath.2010.090353

Matrix Metalloproteinases (MMPs)

MMPs degrade collagen of the extracellular matrix, contributing to tissue remodeling as well as tumor invasion and metastasis. Serum levels of MMP-2 are higher in patients with PTC and differentiated thyroid carcinoma (DTC) compared to those with benign thyroid disease and healthy controls1,2, and high MMP-2 levels are an independent risk factor for metastasis and worse clinical outcomes1. MMP-9 is also higher and correlates with metastasis in DTC patients2.

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  1. Shi Y, Su C, Hu H, et al. Serum MMP-2 as a potential predictive marker for papillary thyroid carcinoma. PLoS One. 2018;13(6):e0198896. Published 2018 Jun 27. doi:10.1371/journal.pone.0198896
  2. Zhang WJ, Song B, Yang T. MMP-2, MMP-9, TIMP-1, and TIMP-2 in the Peripheral Blood of Patients with Differentiated Thyroid Carcinoma. Cancer Manag Res. 2019;11:10675-10681. Published 2019 Dec 23. doi:10.2147/CMAR.S233776