A different perspective to the tumor microenvironment in periampullary cancers: a neglected ring in tumorogenesis.

Abstract

Aim: There is increasing evidence that, tumor microenvironment plays an important role in the initiation and progression of the tumor and is not only a passive observer. In this study the immunohistochemical staining pattern of the stromal cells in tumor microenvironment which is rarely discussed in the literature, has been demonstrated by considering p53 and HSF1 which are important molecular proteins in tumorogenesis.

Material and Method: Sixty-nine pancreaticoduodenectomy specimens that performed between 2000 and 2012 were re-evaluated in terms of HSF1/P53 expressions in tumor microenvironment and tumoral cells. The findings were statistically analyzed.

Results: In our study, there was a significant difference between tumoral microenvironment and tumoral cells in terms of HSF1 staining (p<0.05). For P53, this difference was observed in pancreatic carcinomas (p<0.05), whereas were not observed in ampullary region carcinomas (p>0.05).

Conclusions: Significant staining of two well-known immunomarkers, such as P53 and HSF1, in stromal cells has further increased the importance of tumor microenvironment in tumorogenesis. 

Keywords

• Tumor microenvironment,pancreas,ampullary,P53

Periampuller kanserlerde tümör mikroçevresine farklı bir bakış açısı: tümörojenezde ihmal edilmiş bir halka

Abstract

Amaç: Tümör mikroçevresinin tümörün başlamasında ve ilerlemesinde önemli bir rol oynadığına ve sadece pasif bir gözlemci olmadığına dair kanıtlar artmaktadır. Bu çalışmada literatürde nadiren tartışılan tümör mikroçevresindeki stromal hücrelerin immünohistokimyasal boyanma paterni, tümörogenezde önemli moleküler proteinler olan p53 ve HSF1 ele alınarak gösterilmiştir.

Gereç ve Yöntem: 2000 ve 2012 yılları arasında yapılan 60 pankreatikoduodenektomi spesmeni, tümör mikroçevresin ve tümöral hücrelerde HSF1/P53 ekspresyonu açısından tekrar değerlendirildi. Bulgular istatistiksel olarak analiz edildi.

Bulgular: Çalışmamızda, tümör mikroçevresi ve tümöral hücreler arasında HSF1 boyaması açısından anlamlı bir fark vardı (p<0.05). P53 için bu fark pankreatik karsinomlarda (p <0.05) gözlenirken, ampullar bölge karsinomlarında gözlenmedi (p> 0.05).

Sonuçlar: P53 ve HSF1 gibi iki iyi bilinen immünmarkerın stromal hücrelerde de belirgin olarak boyanması, tümör mikroçevresinin tümörogenezdeki önemini daha da artırmıştır.

Keywords

• Tümör mikroçevresi,pankreas,ampullary,P53,HSF1

References

1. 1. Ansari D, Chen BC, Dong L, Zhou MT, Andersson R. Pancreatic cancer: Translational research aspects and clinical implications. World J Gastroenterol 2012; 18: 1417-24.
2. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2016; 66: 7-30.
3. 3. Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 2011; 8: 151-60.
4. 4. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19: 1423-37. 5. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144: 646-74.
5. 5. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144: 646-74.
6. 6. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci 2012; 125: 5591-6.
7. 7. Hanahan D, Coussens LM. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309-22.
8. 8. Fukino K, S Lei, M Satoshi, MD Carl, ML George, et al. Combined total genome loss of heterozygosity scan of breast cancer stroma and epithelium reveals multiplicity of stromal targets. Cancer Res 2004; 64: 7231–6.

9. 9. Paterson RF, Thomas MU, Gregory MT, Shaobo Z, Chong-Xian P, et al. Molecular genetic alterations in the laser capture microdissected stroma adjacent to bladder carcinoma. Cancer 2003; 98: 1830–6.
10. 10. Capparelli C, Guido C, Whitaker-Menezes D, Banuccelli G, Balliet R, et al. Autophagy and senescence in cancer associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle 2012; 11: 2285–2302.
11. 11. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2004; 2: E7.
12. 12. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006; 6: 392–401.
13. 13. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012; 12: 401–10.
14. 14. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–48.
15. 15. Pelham RJ, Rodgers L, Hall I, Lucito R, Navin N, et al. Identification of alterations in DNA copy number in host stromal cells during tumor progression. Proc Natl Acad Sci USA 2006; 103: 19848–53.
16. 16. Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, et al. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 2000; 60: 2562–6.
17. 17. Qiu W, Hu M, Sridhar A, Opeskin K, Fox S, et al. No evidence of clonal somatic genetic alterations in cancer associated fibroblasts from human breast and ovarian carcinomas. Nat Genet 2008; 40: 650–5.
18. 18. Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor promoting mammary stromal myofibroblasts. Proceedings of the National Academy of Sciences. 2010; 107: 20009–14.
19. 19. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004; 303: 848–51.
20. 20. Li X, Placencio V, Iturregui JM, Uwamariya C, Sharif-Afshar AR, et al. Prostate tumor progression is mediated by a paracrine TGF-beta/Wnt3a signaling axis. Oncogene 2008; 27: 7118–30.
21. 21. Soussi T, Wiman KG. Shaping genetic alterations in human cancer: The P53 mutation paradigm. Cancer Cell 2007; 12: 303–12.
22. 22. Levine AJ, Oren M. The first 30 years of P53: Growing ever more complex. Nat Rev Cancer 2009; 9: 749–58.
23. 23. Menendez D, Inga A, Resnick MA. The expanding universe of P53 targets. Nat Rev Cancer 2009; 9: 724–37.
24. 24. Wernert N, Locherbach C, Wellmann A, Behrens P, Hugel A. Presence of genetic alterations in microdissected stroma of human colon and breast cancers. Anticancer Res 2001; 21: 2259–64.
25. 25. Fukino K, Shen L, Patocs A, Mutter GL, Eng C. Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma. Jama 2007; 297: 2103–111.
26. 26. Narendran A, Ganjavi H, Morson N, Connor A, Barlow JW, et al. Mutant P53 in bone marrow stromal cells increases VEGF expression and supports leukemia cell growth. Exp Hematol 2003; 31: 693–701.
27. 27. Patocs A, Zhang L, Xu Y, Weber F, Caldes T, et al. Breast cancer stromal cells with P53 mutations and nodal metastases. N Engl J Med 2007; 357: 2543-51.
28. 28. Hasebe T, Okada N, Tamura N, Houjoh T, Akashi-Tanaka S, et al. P53 expression in tumor stromal fibroblasts is associated with the outcome of patients with invasive ductal carcinoma of the breast. Cancer Sci 2009; 100: 2101–8.
29. 29. Khwaja FW, Svoboda P, Reed M, Pohl J, Pyrzynska B, et al. Proteomic identification of the Wt/P53 regulated tumor cell secretome. Oncogene 2006; 25: 7650–61.
30. 30. Ehnfors J, Kost-Alimova M, Persson NL, Bergsmedh A, Castro J, et al. Horizontal transfer of tumor DNA to endothelial cells in vivo. Cell Death Differ 2009; 16: 749–57.