Pankreatik Duktal Adenokarsinomada Ekstrasellüler Matriks Degradasyonu Hedefli Tedavi Yaklaşımları

Yıl 2020, Cilt: 11 Sayı: 2, 260 - 265, 15.06.2020

Furkan Özbalcı , Demet Kaçaroğlu , Nilgün Gürbüz

Öz

Pankreatik duktal adenokarsinoma (PDAC) mortalitesi ve morbiditesi en fazla olan kanser türleri arasında yer almaktadır. PDAC’nin kötü prognozunun nedenleri arasında hücre döngüsünü sağlayan moleküler mekanizmaların bozulması, hücrelerin apoptozise ve kemoterapiye direnç geliştirmesi, hücrelerin tümör mikroçevresiyle etkileşimi sonucu yapısının bozulması, hipoksi oluşumu ve stromal yapının değişimi gösterilebilir. Ekstrasellüler matriksteki proteinlerin yapım ve yıkım hızındaki değişikliklerden dolayı oluşan yoğun fibrotik stroma sırasıyla invazyon, migrasyon, ve metastaz sürecini hızlandırır. İlk olarak kanser hücreleri tarafından sitokin, peptid, mRNA ve protein inhibitörleri içeren eksozomlar salgılanarak fibroblastların ve kollajenlerin doğal yapısının bozulması sonucu kanser ilişkili fibroblastlar ve düzensiz kollajen örgüsü oluşur. Daha sonra hyaluronan sentaz enzimlerinin aktivitesinin aşırı artmasına bağlı olarak sentezlenen hyaluronan birikimi de stromanın yoğunlaşmasında etkilidir. Bununla birlikte endotelyal hücrelerin, pankreatik yıldızsı hücrelerin ve kanser ilişkili fibroblastların salgıladıkları interlökin ve kemokinlere yanıt olarak proteolitik enzimlerin ekpresyonunun artması sonucu kanser hücrelerinin migrasyonu kolaylaşır. Matriks morfolojisinin bozulmasıyla gelişen immunsupresif tümör mikroçevrenin oluşumu PDAC tedavisinde kullanılan immunoterapi ve kemoterapi yöntemlerinin başarı oranını azaltmaktadır. Ekstrasellüler matriks yıkımını arttıran gemsitabin ve paklitaksel gibi kemoterapötik ajanların etkinliğinin arttırılmasına dayalı tedavi stratejileri geliştirilmelidir. Bu kapsamda stromada biriken hyaluronanın parçalanması veya sentezinin inhibisyonu, matriks metalloproteinaz inhibitörleri kullanılarak migrasyonunun engellenmesi, Hedgehod reseptörlerine antagonist monoklonal antikor ve küçük peptidlerin kullanımı ile fibrotik stromanın oluşumunu engellenmesi, tümör mikroçevresine makrofajin filtrasyonunu arttırmak için CD40 agonistleri kullanımı gibi terapötik yaklaşımların geliştirilmesi için faz çalışmaları önem kazanarak devam etmektedir. Bu derlemede, pankreatik tümör mikroçevresinin anlaşılması, ekstrasellüler matriks degradasyonunu etkileyen moleküler mekanizmaların açıklanması amaçlanmış olup, çalışmamızın böylelikle ekstrasellüler matriks hedefli yeni terapötik stratejilerin geliştirilmesi ile ilgili araştırmalara ışık tutacağına inanmaktayız.

Anahtar Kelimeler

PDAC, Ekstrasellüler Matriks, ECM, Metastaz, Terapötik Yaklaşım

Kaynakça

• Kim VM, Ahuja N. Early detection of pancreatic cancer. Chin J Cancer Res. 2015;27(4):321–31.
• Cao Z, Liu C, Xu J, You L, Wang C, Lou W, et al. Plasma microRNA panels to diagnose pancreatic cancer: Results from a multicenter study. Oncotarget. 2016;7(27):41575-83.
• Zhang JQ, Chen S, Gu JN, Zhu Y, Zhan Q, Cheng DF, et al. MicroRNA-300 promotes apoptosis and inhibits proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/β-catenin signaling pathway by targeting CUL4B in pancreatic cancer cells. J Cell Biochem. 2018;119(1):1027-40.
• Provenzano PP, Hingorani SR. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer. 2013;108(1):1-8.
• Carr RM, Fernandez‐Zapico ME. Pancreatic cancer microenvironment, to target or not to target? EMBO Mol Med. 2016;8(2):80-2.
• Zhao T, Jiang W, Wang X, Wang H, Zheng C, Li Y,et al. ESE3 inhibits pancreatic cancer metastasis by upregulating E-cadherin. Cancer Res. 2017;77(4):874-85.
• Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The Pancreas Cancer Microenvironment. Clin Cancer Res. 2012;18(16):4266-76.
• Nielsen MFB, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol. 2016;22(9):2678-700.
• Miao F, Zhu J, Chen Y, Tang N, Wang X, Li X. MicroRNA-183-5p promotes the proliferation, invasion and metastasis of human pancreatic adenocarcinoma cells. Oncol Lett. 2016;11(1):134-40.
• Gharibi A, Adamian Y, Kelber J. Cellular and molecular aspects of pancreatic cancer. Acta Histochem. 2017;118(3):305-16.
• Whatcott CJ, Diep CH, Jiang P, Watanabe A, Lobello J, Sima C, et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res. 2015;21(15):3561-8.
• Binker MG, Binker-Cosen MJ, Binker-Cosen AA, Cosen-Binker LI. Microenvironmental factors and extracellular matrix degradation in Pancreatic cancer. J Pancreas. 2014;15(4):280–5.
• Dhayat SA, Traeger MM, Rehkaemper J, Stroese AJ, Steinestel K, Wardelmann E, et al. Clinical impact of epithelial-to-mesenchymal transition regulating microRNAs in pancreatic ductal adenocarcinoma. Cancers. 2018;10(9):1-20.
• Xiong J, Wang D, Wei A, Lu H, Tan C, Li A, et al. Deregulated expression of miR-107 inhibits metastasis of PDAC through inhibition PI3K/Akt signaling via caveolin-1 and PTEN. Exp Cell Res. 2017;361(2):316–23.
• Ashour AA, Gurbuz N, Neslihan S, Abdel-aziz AH. Elongation factor-2 kinase regulates TG2 / β1 integrin / Src / uPAR pathway and epithelial mesenchymal transition mediating pancreatic cancer cells invasion. J Cell Mol Med. 2014;18(11):2235–51.
• Venning FA, Wullkopf L, Erler JT. Targeting ECM disrupts cancer progression. Front Oncol. 2015;5(OCT):1-15.
• Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014;15(12):1243-53.
• Weniger M, Honselmann KC, Liss AS. The extracellular matrix and pancreatic cancer: A complex relationship. Cancers. 2018;10(9):1-20.
• Karsdal MA, Nielsen SH, Leeming DJ, Langholm LL, Nielsen MJ, Manon-Jensen T, et al. The good and the bad collagens of fibrosis-Their role in signaling and organ function. Adv Drug Deliv Rev. 2017;1(121):43-56.
• Murakami T, Hiroshima Y, Matsuyama R, Homma Y, Hoffman RM, Endo I. Role of the tumor microenvironment in pancreatic cancer. Ann Gastroenterol Surg. 2019;3(2):130-7.
• Zhao S,Chen C, Chang K, Karnad A, Jagirdar J, Kumar AP, Freeman JW. CD44 expression level and isoform contributes to pancreatic cancer cell plasticity, invasiveness, and response to therapy. Clin Cancer Res. 2016;22(22):5592-604.
• Shan T, Chen S, Chen X, Lin WR, Li W, Ma J, et.al. Cancer associated fibroblasts enhance pancreatic cancer cell invasion by remodeling the metabolic conversion mechanism. Oncol Rep. 2017;37(4):1971-79.
• Von Ahrens D, Bhagat TD, Nagrath D, Maitra A, Verma A. The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol. 2017;10(1):76.
• Hao J. HIF-1 is a critical target of pancreatic cancer. Oncoimmunology. 2015;4(9):e1026535.
• Vandooren J, Opdenakker G, Loadman PM, Edwards DR. Proteases in cancer drug delivery. Adv Drug Deliv Rev. 2016;1(97):144-155.
• Sternlicht MD, Werb Z. How Matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463-516.
• Jabłońska-Trypuć A , Matejczyk M, Rosochacki S. Matrix metalloproteinases, the main extracellularmatrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem. 2016;31(Sup1):177-183.
• Kabacaoglu D, Ciecielski KJ, Ruess DA, Algül H. Immune check point inhibition for pancreatic ductal adenocarcinoma: current limitations and future options. Front Immunol. 2018;15(9):1878.
• Tjomsland V, Pomianowska E , Aasrum M, Sandnes D, Verbeke CS, Gladhaug IP. Profile of MMP and TIMP expression in human pancreatic stellate cells: regulationby IL-1α and TGF-β and implications for migration of Pancreatic cancer cells. Neoplasia. 2016;18(7):447-56.
• Díaz-López A , Moreno-Bueno G , Cano A. Role of microRNA in Epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Manag Res. 2014;6(1):205-16.
• Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness inhibiting microRNAs. Nature Cell Biol. 2009;11(12):1487–95.
• Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8(3):241-54.
• Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, et.al. Lysyloxidase is essential for hypoxia-induced metastasis. Nature. 2006;440(7088):1222-6.
• Lee J, Condello S, Yakubov B, Emerson R, Caperell Grant A, Hitomi K, et.al. Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression. Clin Cancer Res. 2015;21(19):4482-93.
• Bonnans C, Chou J, Werb Z. Remodelling the extracellularmatrix in development and disease. Nat Rev Mol Cell Biol. 2014;15(12):786-801.
• D'Costa Z, Jones K, Azad A, Van Stiphout R, Lim SY, Gomes AL, et.al. Gemcitabine-Induced TIMP1 Attenuates Therapy Response and Promotes Tumor Growth and Liver Metastasis in Pancreatic Cancer. Cancer Res. 2017;77(21):5952-62.
• Rath N, Olson MF. Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy. EMBO Rep. 2012;13(10):900-8.
• Begum A, Ewachiw T, Jung C, Huang A, Norberg KJ, Marchionni L, et.al. The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma. PLoS One. 2017;12(7):e0180181.
• Sato N, Cheng XB, Kohi S, Koga A, Hirata K. Sinica B. Targeting hyaluronan for the treatment of pancreatic ductal adenocarcinoma. Acta Pharmaceutica. 2016;6(2):101-5.
• Hajime M, Shuichi Y, Makoto N, Masanori Y, Ikuko K, Atsushi K, et.al. Inhibitory effect of 4‐methylesculetin on hyaluronan synthesis lows the development of Human pancreatic cancer in vitro and in nude mice. Int J Cancer. 2007;120(12):2704-9.
• Morohashi H, Kon A, Nakai M, Yamaguchi M, Kakizaki I, Yoshihara S, et.al. Study of hyaluronan synthase inhibitor, 4-methylumbelliferone derivatives on human pancreatic cancer cell (KP1-NL). Biochem Biophy Res Commun. 2006;345(4):1454-9.
• Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62(1):112-20.
• Wong KM , Horton KJ, Coveler AL , Hingorani SR, Harris WP. Targeting the tumor stroma: the biology and clinical development of pegylated recombinant human hyaluronidase (PEGPH20). Curr Oncol Rep. 2017;19(7):47.
• Aslan M, Shahbazi R, Ulubayram K, Ozpolat B. Targeted therapies for pancreatic cancer and hurdles ahead. Anticancer Res.2018;38(12):6591-606.
• Liu, Y, Cao X. The origin and function of tumor associated macrophages. Cel Mol Immunol. 2015;12(1):1-4.
• Long KB, Gladney WL, Tooker GM, Graham K, Fraietta JA, Beatty GL. IFN-γ and CCL2 cooperatetore direct tumor infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov. 2016;6(4):400-13.
• Vonderheide RH, Martin JG. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19(5):1035-43.
• Assaf Z, Lilach K, Omer A, Maria P, Mohammed A, Zvi Y, et.al. Collagenase nanoparticles enhance the penetration of drugs into pancreatic tumors. ACS Nano .2019;13(10):11008-21.
• Alvarez MA, Freitas JP, Hussain SM, Glazer ES. TGF-β Inhibitors in Metastatic Pancreatic Ductal Adenocarcinoma. J Gastrointest Cancer. 2019;50(2):207-13.
• Winer A, Adams S, Mignatti P. Matrix metalloproteinase inhibitors in Cancer therapy: turning past failures into future successes. Mol Cancer Ther. 2018;17(6):1147-55.