본문 바로가기
KERD
논문KCI 등재

Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류병리학

초록

Background: SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC. Methods: We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs. Results: A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p = .042) and 7-year cancerspecific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p = .022). Conclusions: We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

Abstract

Background: SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC. Methods: We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs. Results: A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p = .042) and 7-year cancerspecific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p = .022). Conclusions: We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

참고문헌 (52)

  1. Bray F, "Global cancer statistics 2018 : GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries", CA Cancer J Clin, 68, pp.394~424 (2018)
  2. Zhao M, "The role of TGF-beta", SMAD4 signaling in cancer, 2018, pp.14, 111~123
  3. Schutte M., "DPC4", SMAD4 gene alterations in human cancer, and their functional implications, 1999, pp.10(Suppl 4), 56~59
  4. Du Y, "Meta-analysis of the prognostic value of smad4 immunohistochemistry in various cancers", PLoS One, 9, pp.e110182~ (2014)
  5. Wang JD, "Clinicopathological significance of SMAD4 loss in pancreatic ductal adenocarcinomas : a systematic review and meta-analysis", Oncotarget, 8, pp.16704~16711 (2017)
  6. Kouvidou C, "Expression of Smad4 and TGF-beta2 in colorectal carcinoma", Anticancer Res, 26, pp.2901~2907 (2006)
  7. Xu WQ, "Expression of TGFbeta1, TbetaRII and Smad4 in colorectal carcinoma", Exp Mol Pathol, 82, pp.284~291 (2007)
  8. Bacman D, "TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma : a retrospective study", BMC Cancer, 7, pp.156~ (2007)
  9. Isaksson-Mettaväinio M, "High SMAD4 levels appear in microsatellite instability and hypermethylated colon cancers, and indicate a better prognosis", Int J Cancer, 131, pp.779~788 (2012)
  10. Voorneveld PW, "Evaluation of the prognostic value of pSMAD immunohistochemistry in colorectal cancer", Eur J Cancer Prev, 22, pp.420~424 (2013)
  11. Kozak MM, "Smad4 inactivation predicts for worse prognosis and response to fluorouracil-based treatment in colorectal cancer", J Clin Pathol, 68, pp.341~345 (2015)
  12. Yan P, "Reduced expression of SMAD4is associated with poor survival in colon cancer", Clin Cancer Res, 22, pp.3037~3047 (2016)
  13. Jain S, "Association of overexpression of TIF1gamma with colorectal carcinogenesis and advanced colorectal adenocarcinoma", World J Gastroenterol, 17, pp.3994~4000 (2011)
  14. Handra-Luca A, "SMAD4 protein expression and cell proliferation in colorectal adenocarcinomas", Virchows Arch, 459, pp.511~519 (2011)
  15. 정유민, "The Smad4", PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma, 2018, pp.52(1), 37~44[DOI]
  16. Oyanagi H, "SMAD4 alteration associates with invasive-front pathological markers and poor prognosis in colorectal cancer", Histopathology, 74, pp.873~882 (2019)
  17. Wasserman I, "SMAD4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance", Clin Cancer Res, 25, pp.1948~1956 (2019)
  18. Alhopuro P, "SMAD4 levels and response to 5-fluorouracil in colorectal cancer", Clin Cancer Res, 11, pp.6311~6316 (2005)
  19. Boulay JL, "SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer", Br J Cancer, 87, pp.630~634 (2002)
  20. Alazzouzi H, "SMAD4 as a prognostic marker in colorectal cancer", Clin Cancer Res, 11, pp.2606~2611 (2005)
  21. Isaksson-Mettavainio M, "SMAD4", DPC4 expression and prognosis in human colorectal cancer, 2006, pp.26, 507~510
  22. Mesker WE, "Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients", Cell Oncol, 31, pp.169~178 (2009)
  23. Baraniskin A, "Prognostic value of reduced SMAD4 expression in patients with metastatic colorectal cancer under oxaliplatin-containing chemotherapy : a translational study of the AIO colorectal study group", Clin Colorectal Cancer, 10, pp.24~29 (2011)
  24. Wang C, "High expression of COUP-TF II cooperated with negative Smad4 expression predicts poor prognosis in patients with colorectal cancer", Int J Clin Exp Pathol, 8, pp.7112~7121 (2015)
  25. Coates RF, "Significance of positive and inhibitory regulators in the TGF-beta signaling pathway in colorectal cancers", Hum Pathol, 66, pp.34~39 (2017)
  26. Xie W, "Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis", Cancer J, 9, pp.302~312 (2003)
  27. Gulubova M, "Role of TGF-beta1, its receptor TGFbetaRII, and Smad proteins in the progression of colorectal cancer", Int J Colorectal Dis, 25, pp.591~599 (2010)
  28. Chun HK, "Low expression of transforming growth factor beta-1 in cancer tissue predicts a poor prognosis for patients with stage III rectal cancers", Oncology, 86, pp.159~169 (2014)
  29. Voorneveld PW, "A Meta-analysis of SMAD4 immunohistochemistry as a prognostic marker in colorectal cancer", Transl Oncol, 8, pp.18~24 (2015)
  30. Zhang B, "Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway", Br J Cancer, 110, pp.946~957 (2014)
  31. Voorneveld PW, "The BMP pathway either enhances or inhibits the Wnt pathway depending on the SMAD4and p53 status in CRC", Br J Cancer, 112, pp.122~130 (2015)
  32. Chow E, "A review of juvenile polyposis syndrome", J Gastroenterol Hepatol, 20, pp.1634~1640 (2005)
  33. Ahn BK, "Smad4 may help to identify a subset of colorectal cancer patients with early recurrence after curative therapy", Hepatogastroenterology, 58, pp.1933~1936 (2011)
  34. Bae JM, "Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system", Br J Cancer, 116, pp.1012~1020 (2017)
  35. Bankhead P, "QuPath : open source software for digital pathology image analysis", Sci Rep, 7, pp.16878~ (2017)
  36. Bae JM, "Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients", World J Gastroenterol, 21, pp.1457~1467 (2015)
  37. Boland CR, "A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer", Cancer Res, 58, pp.5248~5257 (1998)
  38. Weisenberger DJ, "CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer", Nat Genet, 38, pp.787~793 (2006)
  39. Jung B, "Transforming growth factor beta superfamily signaling in development of colorectal cancer", Gastroenterology, 152, pp.36~52 (2017)
  40. Salovaara R, "Frequent loss of SMAD4", DPC4 protein in colorectal cancers, 2002, pp.51, 56~59
  41. Ilyas M, "Transforming growth factor beta stimulation of colorectal cancer cell lines : type II receptor bypass and changes in adhesion molecule expression", Proc Natl Acad Sci U S A, 96, pp.3087~3091 (1999)
  42. Deacu E, "Activin type II receptor restoration in ACVR2-deficient colon cancer cells induces transforming growth factor-beta response pathway genes", Cancer Res, 64, pp.7690~7696 (2004)
  43. Baker K, "Microsatellite unstable colorectal cancer cell lines with truncating TGFbetaRII mutations remain sensitive to endogenous TGFbeta", J Pathol, 213, pp.257~265 (2007)
  44. de Miranda NF, "Transforming growth factor beta signaling in colorectal cancer cells with microsatellite instability despite biallelic mutations in TGFBR2", Gastroenterology, 148, pp.1427.e8~1437.e8 (2015)
  45. Barros R, "Key elements of the BMP", SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines, 2008, pp.215, 411~420
  46. Barros R, "Juvenile polyps have gastric differentiation with MUC5AC expression and downregulation of CDX2 and SMAD4", Histochem Cell Biol, 131, pp.765~772 (2009)
  47. Savagner P., "The epithelial-mesenchymal transition (EMT) phenomenon", Ann Oncol, 21(Suppl 7), pp.vii89~vii92 (2010)
  48. Ioannou M, "Smad4 and epithelial-mesenchymal transition proteins in colorectal carcinoma : an immunohistochemical study", J Mol Histol, 49, pp.235~244 (2018)
  49. Deckers M, "The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells", Cancer Res, 66, pp.2202~2209 (2006)
  50. Itatani Y, "Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis", Gastroenterology, 145, pp.1064.e11~1075.e11 (2013)
  51. Inamoto S, "Loss of SMAD4 promotes colorectal cancer progression by accumulation of myeloid-derived suppressor cells through the CCL15-CCR1 chemokine axis", Clin Cancer Res, 22, pp.492~501 (2016)
  52. Yamamoto T, "Loss of SMAD4 promotes lung metastasis of colorectal cancer by accumulation of CCR1+ tumorassociated neutrophils through CCL15-CCR1 axis", Clin Cancer Res, 23, pp.833~844 (2017)

관련 논문AI추천

The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma김예슬, 민경환, 방성식, 백승삼, 양정호, 위영찬, 장기석, 정유민대한병리학회 · Journal of Pathology and Translational Medicine2018 · 제52권 제1호DPC4 Expression in the Small Intestinal Adenocarcinomas김준미, 배영경, 배한익, 유은실, 윤길숙, 이선재, 장기택, 홍승모, The Korean Small Intestinal Cancer Study Group대한병리학회 · Journal of Pathology and Translational Medicine2012 · 제46권 제5호Clinicopathological Significance of SMAD4 Expression in Breast Cancer정민성, Jun-Seok Woo, Seung Sam Paik한국유방암학회 · Journal of Breast Disease2019 · 제7권 제2호Pathologic Factors Associated with Prognosis after Adjuvant Chemotherapy in Stage II/III Microsatellite-Unstable Colorectal Cancers강경훈, 김정호, 배정모, 오현정, 이혜승대한병리학회 · Journal of Pathology and Translational Medicine2015 · 제49권 제2호Expression of E-cadherin and β-catenin is Altered at Tumor Budding Sites, Whose Number is Associated with the Progression of Colorectal Carcinoma장태정대한병리학회 · Journal of Pathology and Translational Medicine2009 · 제43권 제6호Clinicopathologic Characteristics of Left-Sided Colon Cancers with High Microsatellite Instability김상겸, 김현기, 김호근, 박영년, 송시영, 최준정대한병리학회 · Journal of Pathology and Translational Medicine2009 · 제43권 제5호

이 간행물의 다른 논문 (10건)