Evaluation of tissue expressions of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in ovarian neoplasms

Background: Even the slightest bit of evidencehave demonstrated that elevated expressions of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) play critical roles in tumor progression in many malignant diseases. But still a little is known about their effects on ovarian carcinogenesis. In this retrospective study, we havetargeted to investigate the positivity of KIM-1 and NGAL (if any) in a spectrum of ovarian surface epithelial neoplasms. Methods: Herein we have assessed the prognostic values of KIM-1 and NGAL tissue expressions and their relations with some clinicopathologic parameters of 128 cases with ovarian neoplasms. Results: This study group consists of cases of 34 (26.6%) benign, and 10 (7.8%) borderline serous tumors, 29 (22.7%) serous, 38 (29.7%) endometrioid and 17 (13.3%) mucinous carcinomas. KIM-1 expression was found in both tumor and inflammatory cells, but NGAL expression was detected only in inflammatory cells. Although it is known that KIM-1 biomarker is expressed at a higher rate in carcinoma cases compared to benign tumors, due to the limited number of cases any statistically significant intergroup difference could not be observed (p = 0.217). Besides, NGAL-positive inflammatory cells were detected at a statistically significantly higher rate in cases with borderline serous tumors and carcinomas (p = 0.003). Conclusions: Herein we have shown the presence of a correlation between infiltrationof NGAL—positive inflammatory cells and malignant behavior of ovarian neoplasms. In addition, we have detected the strong cytoplasmic expression of KIM-1 (or its synonym T-cell immunoglobulin and mucin domain/TIM-1), in more than one-third of the malignant ovarian neoplasms which provides supportive evidence favoringthe use of anti-TIM1 immunotherapies in the treatment of patients with KIM-1 positive ovarian neoplasms.

Ovarian tumors; KIM-1; TIM-1; anti-TIM1 drugs; NGAL

[1] Zhang PL, Mashni JW, Sabbisetti VS, Schworer CM, Wilson GD, Wolforth SC, et al. Urine kidney injury molecule-1: a potential non-invasive biomarker for patients with renal cell carcinoma. International Urology and Nephrology. 2014; 46: 379–388.

[2] Ersavaş S, Diniz G, Yildirim HT, Koca Y, Kahraman DS, Ayaz D, et al. Expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in Wilms tumor. Turkish Journal of Pathology. 2016; 32: 158–163.

[3] Kahraman DS, Diniz G, Sayhan S, Ersavas S, Ayaz D, Keskin E, et al. Over expressions of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in human uterine cervical neoplasms enhance tumor invasion. European Journal of Gynaecological Oncology. 2021; 42: 148–153.

[4] Thomas LJ, Vitale L, O’Neill T, Dolnick RY, Wallace PK, Minderman H, et al. Development of a novel antibody-drug conjugate for the potential treatment of ovarian, lung, and renal cell carcinoma expressing TIM-1. Molecular Cancer Therapeutics. 2016; 15: 2946–2954.

[5] McGregor BA, Gordon M, Flippot R, Agarwal N, George S, Quinn DI, et al. Safety, and efficacy of CDX-014, an antibody-drug conjugate directed against T cell immunoglobulin mucin-1 in advanced renal cell carcinoma. Investigational New Drugs. 2020; 38: 1807–1814.

[6] Manzano A, Ocaña A. Antibody-drug conjugates: a promising novel therapy for the treatment of ovarian cancer. Cancers. 2020; 12: 2223.

[7] Sinha V, Vence LM, Salahudeen AK. Urinary tubular protein-based biomarkers in the rodent model of cisplatin nephrotoxicity: a comparative analysis of serum creatinine, renal histology, and urinary kim-1, NGAL, and NAG in the initiation, maintenance, and recovery phases of acute kidney injury. Journal of Investigative Medicine. 2013; 61: 564–568.

[8] Zhang T, Widdop RE, Ricardo SD. Transition from acute kidney injury to chronic kidney disease: mechanisms, models, and biomarkers. American Journal of Physiology-Renal Physiology. 2024; 327: F788–F805.

[9] Kamianowska M, Szczepański M, Sawicka E, Bebko B, Wasilewska A. The tubular damage markers: neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in newborns with exposure to maternal diabetes during pregnancy. Archives of Medical Science. 2020; 20: 762–768.

[10] Stanski NL, Rodrigues CE, Strader M, Murray PT, Endre ZH, Bagshaw SM. Precision management of acute kidney injury in the intensive care unit: current state of the art. Intensive Care Medicine. 2023; 49: 1049–1061.

[11] Roli L, Pecoraro V, Trenti T. Can NGAL be employed as prognostic and diagnostic biomarker in human cancers? A systematic review of current evidence. The International Journal of Biological Markers. 2017; 32: e53–e61.

[12] Woziwodzka K, Małyszko J, Koc-Żórawska E, Żórawski M, Dumnicka P, Jurczyszyn A, et al. Renal impairment detectors: IGFBP-7 and NGAL as tubular injury markers in multiple myeloma patients. Medicina. 2021; 57: 1348.

[13] Sayhan S, Diniz G, Karadeniz T, Ayaz D, Kahraman DS, Gokcu M, et al. Expression of caveolin-1 in peritumoral stroma is associated with histological grade in ovarian serous tumors. Ginekologia Polska. 2015; 86: 424–428.

[14] Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nature Reviews Clinical Oncology. 2013; 10: 211–224.

[15] Kahraman DS, Diniz G, Sayhan S, Sayar C, Ayaz D, Gokcu M, et al. The prognostic significance of PD-L1 and FOXP3 expressions in tumor cells and the tumor microenvironment of ovarian epithelial tumors. International Journal of Clinical and Experimental Pathology. 2018; 11: 3884–3890.

[16] Wei CT, Tsai IT, Wu CC, Hung WC, Hsuan CF, Yu TH, et al. Elevated plasma level of neutrophil gelatinase-associated lipocalin (NGAL) in patients with breast cancer. International Journal of Medical Sciences. 2021; 18: 2689–2696.

[17] Candido S, Maestro R, Polesel J, Catania A, Maira F, Signorelli SS, et al. Roles of neutrophil gelatinase- associated lipocalin (NGAL) in human cancers. Oncotarget. 2014; 5: 1576–1594.

[18] Olar MP, Iacobescu M, Bolboacă SD, Pojoga C, Moșteanu O, Seicean R, et al. Neutrophil gelatinase-associated lipocalin for the differentiation of mucinous pancreatic cystic lesions. International Journal of Molecular Sciences. 2024; 25: 3224.

[19] Ruiz-Morales JM, Dorantes-Heredia R, Arrieta O, Chávez-Tapia NC, Motola-Kuba D. Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in lung adenocarcinoma. Tumour Biology. 2015; 36: 3601–3610.

[20] Monisha J, Roy NK, Padmavathi G, Banik K, Bordoloi D, Khwairakpam AD, et al. NGAL is downregulated in oral squamous cell carcinoma and leads to increased survival, proliferation, migration and chemoresistance. Cancers. 2018; 10: 228.

[21] Liu F, Li N, Yang W, Wang R, Yu J, Wang X. The expression analysis of NGAL and NGALR in clear cell renal cell carcinoma. Gene. 2018; 676: 269–278.

[22] Valashedi MR, Roushandeh AM, Tomita K, Kuwahara Y, Pourmohammadi-Bejarpasi Z, Kozani PS, et al. CRISPR/Cas9-mediated knockout of Lcn2 in human breast cancer cell line MDA-MB-231 ameliorates erastin-mediated ferroptosis and increases cisplatin vulnerability. Life Sciences. 2022; 304: 120704.

[23] Wang Y, Martin TA, Jiang WG. HAVcR-1 expression in human colorectal cancer and its effects on colorectal cancer cells in vitro. Anticancer Research. 2013; 33: 207–214.

[24] Su S, Yin L. Application of pelvic magnetic resonance imaging scan combined with serum pyruvate kinase isozyme M2, neutrophil gelatinase-associated lipocalin, and soluble leptin receptor detection in diagnosing endometrial carcinoma. Contrast Media & Molecular Imaging. 2022; 2022: 7197505.

[25] Cheng Z, Li H, Chen C, Lv X, Zuo E, Xie X, et al. Application of serum SERS technology based on thermally annealed silver nanoparticle composite substrate in breast cancer. Photodiagnosis and Photodynamic Therapy. 2023; 41: 103284.

[26] Zeng Q, Cheng C, Chen C, Song H, Li M, Yan J, et al. Serum Raman spectroscopy combined with convolutional neural network for rapid diagnosis of HER2-positive and triple-negative breast cancer. Spectrochimica Acta 2023 Part A: Molecular and Biomolecular Spectroscopy. 2023; 286: 122000.

[27] Dai J, Ashrafizadeh M, Aref AR, Sethi G, Ertas YN. Peptide-functionalized, -assembled and -loaded nanoparticles in cancer therapy. Drug Discovery Today. 2024; 29: 103981.

[28] Ma X, Cheng H, Hou J, Jia Z, Wu G, Lü X, et al. Detection of breast cancer based on novel porous silicon Bragg reflector surface-enhanced Raman spectroscopy-active structure. Chinese Optics Letters. 2020; 18: 051701.

[29] Monisha J, Padmavathi G, Bordoloi D, Roy NK, Kunnumakkara AB. Neutrophil gelatinase-associated lipocalin (NGAL): a promising biomarker for cancer diagnosis and a potential target for cancer therapeutics. Journal of Cell Science & Molecular Biology. 2014; 1: 106.

[30] Lim R, Ahmed N, Borregaard N, Riley C, Wafai R, Thompson EW, et al. Neutrophil gelatinase-associated lipocalin (NGAL) an early-screening biomarker for ovarian cancer: NGAL is associated with epidermal growth factor-induced epithelio-mesenchymal transition. International Journal of Cancer. 2007; 120: 2426–2434.

[31] Živalj M, Van Ginderachter JA, Stijlemans B. Lipocalin-2: a nurturer of tumor progression and a novel candidate for targeted cancer therapy. Cancers. 2023; 15: 5159.

[32] Hunsicker O, Feldheiser A, Weimann A, Liehre D, Sehouli J, Wernecke KD, et al. Diagnostic value of plasma NGAL and intraoperative diuresis for AKI after major gynecological surgery in patients treated within an intraoperative goal-directed hemodynamic algorithm: a substudy of a randomized controlled trial. Medicine. 2017; 96: e7357.

[33] Florova B, Rajdl D, Racek J, Fiala O, Matejka VM, Trefil L. NGAL, albumin and cystatin C during cisplatin therapy. Physiological Research. 2020; 69: 307–317.