Tissue interstitial fluid (TIF), as the liquid microenvironment of cancer cells, reflects the molecular imprint of proteins that are related to cancer and represents a reliable link among tumor markers expression and body fluids circulation. Since tumors have a high degree of immunogenicity, many tumor markers released in the TIF, once drained into local lymph nodes, may act as tumor-associated antigens (TAAs) and activate B-cells which in turn generate tumor antigen-specific antibodies. The generation of these antibodies leads to a very effective and specific biological amplification of a tumor marker. Therefore, their serological identification could be an effective strategy for the early diagnosis of a cancer.
Late clinical presentation and limited treatment options make the early diagnosis of intrahepatic cholangiocarcinoma (iCCA) by noninvasive methods a current clinical challenge. Here, as preliminary results, we unveil a peculiar proteome profile of TIF isolated in iCCA patients. This analysis represents a valuable molecular platform in the characterization of both immune and non-immune iCCA-associated proteins. Therefore, driven by our preliminary results, we designed the present proposal in search of effective circulating biomarkers and potential therapeutic targets. Particularly, we firstly aim to quantify circulating tumor markers from the proteins found to be aberrantly expressed in the iCCA TIF. Then, by immunoproteomic approach, we aim to identify TAAs in the TIF. Finally, identified iCCA-specific antigens will be tested for their capability to isolate and quantify specific antibodies in serum. The ultimate scope of this project will be the development of a specific and sensitive biomarkers panel by combining tumor markers and tumor-specific antibodies.
We believe that obtained results could improve significantly the management of iCCA. This aspect is particularly relevant for the Italian National System. In fact, in the last ten years, incidence and mortality rate of tumors of the biliary tract show an increase of about 3% per year [16]. This results in a high impact for both patients and the national public health system. In fact, clinical, laboratory, endoscopic, and radiographic analyses are invasive procedures and require high costs of hospitalization. In light of all these considerations, a diagnostic test, based on circulating tumor markers and TAAs-specific antibodies could offer several advantages also in terms of economy, tolerability and monitoring. We believe, therefore, that our study will draw a new interest not only in search of tools for the early iCCA detection, but also in identifying potential molecular targets for therapy. In fact, tumor up-regulated proteins unveiled in our TIF proteomics analysis may have a wide range of implications, such as the reduction of immunosuppressive iCCA microenvironment, the inhibition of blood vessel formation and tumor cells spreading by lymph vessels as well as any identified TAAs may have an impact on cancer vaccine development.
References:
1. Rizvi S and Gores GJ. Gastroenterology. Pathogenesis, diagnosis, and management of cholangiocarcinoma. 2013;145:1215-29.
2. Rizvi S et al. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018 Feb;15(2):95-111.
3. Wang M et al. Role of tumor microenvironment in tumorigenesis. J Cancer. 2017; 8(5): 761¿773.
4. De Palma M et al. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017 Aug;17(8):457-474.
5. Lim B et al. Inflammatory breast cancer biology: the tumour microenvironment is key. Nat Rev Cancer. 2018 Aug;18(8):485-499.
6. Rodrigues da Cunha B et al. Cellular Interactions in the Tumor Microenvironment: The Role of Secretome. J Cancer. 2019; 10(19): 4574¿4587.
7. Meeusen E et al. Secreted Tumor Antigens - Immune Biomarkers for Diagnosis and Therapy. Proteomics. 2017 Dec;17(23-24).
8. Brivio S et al. Tumor reactive stroma in cholangiocarcinoma: The fuel behind cancer aggressiveness. World J Hepatol. 2017 Mar 28;9(9):455-468
9. Fabris L et al. The tumour microenvironment and immune milieu of cholangiocarcinoma. Liver Int. 2019 May;39 Suppl 1:63-78.
10. Chen z et al. J Cell Mol Med. 2019 Jan;23(1):59-69. The role of tumour microenvironment: a new vision for cholangiocarcinoma.
11. Carpino G et al. Matrisome analysis of intrahepatic cholangiocarcinoma unveils a peculiar cancer-associated extracellular matrix structure. Clin Proteomics. 2019 Oct 30;16:37.
12. Sun W et al. Quantitative Proteomics Analysis of Tissue Interstitial Fluid for Identification of Novel Serum Candidate Diagnostic Marker for Hepatocellular Carcinoma. Sci Rep. 2016 May 24;6:26499. doi: 10.1038/srep26499.
13. Chalasani N et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012 Jun;55(6):2005-23.
14. Stacker S.A et al. The role of tumor lymphangiogenesis in metastasic spread. FASEB J. 2002;16, 922¿934.
15. Amini N et al. Management of lymph nodes during resection of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: a systematic review. J Gastrointest Surg. 2014;18:2136¿48.
16. Alvaro D et al. Descriptive epidemiology of cholangiocarcinoma in Italy. Dig Liver Dis. 2010 Jul;42(7):490-5.