Podoplanin Expression in Early-Stage Colorectal Cancer-Associated Fibroblasts and Its Utility As a Diagnostic Marker for Colorectal Lesions

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2024 Oct 25

PMID 39451200

Authors

Shuichi Tsukamoto

Takayuki Kodama

Mari Nishio

Manabu Shigeoka

Tomoo Itoh

Hiroshi Yokozaki

Yu-Ichiro Koma

Affiliations

Soon will be listed here.

Abstract

(Background) Cancer-associated fibroblasts (CAFs) are major cancer stromal components. CAFs have diverse functions and cell origins. Podoplanin (PDPN), a lymphatic vessel marker, is also a CAF marker in certain cancers. On daily diagnosis of early colorectal carcinoma (CRC), PDPN upregulation in the stroma is often encountered, suggesting PDPN-positive CAFs have emerged. However, PDPN-positive CAFs in early CRC have not been studied well. (Methods) On immunohistochemistry, PDPN expression in the lamina propria or stroma of adenomas, early CRCs, and neuroendocrine tumors, their normal neighbors, and non-neoplastic colorectal lesions were compared. Single-cell RNA sequencing (scRNA-seq) of CRC was used to explore CAFs' cell origins. (Results) Reticular cells or pericryptal fibroblasts in the lamina propria of adenomas and early CRCs showed higher PDPN expression than did normal mucosae and non-neoplastic lesions ( < 0.01). Pericryptal PDPN expression was a diagnostic feature of adenomas and early CRCs. scRNA-seq of CRCs highlighted that CAFs had distinctly higher , , and expression, unlike well-known CAFs characterized by high , or expression. (Conclusions) We demonstrated that pericryptal fibroblasts and reticular cells in the lamina propria are origins of early-stage CRC CAFs and thus have potential as a diagnostic marker for distinguishing colorectal non-neoplastic from neoplastic lesions.

References

Miyako S, Koma Y, Nakanishi T, Tsukamoto S, Yamanaka K, Ishihara N . Periostin in Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression by Enhancing Cancer and Stromal Cell Migration. Am J Pathol. 2024; 194(5):828-848. DOI: 10.1016/j.ajpath.2023.12.010. View

Brosens L, Montgomery E, Bhagavan B, Offerhaus G, Giardiello F . Mucosal prolapse syndrome presenting as rectal polyposis. J Clin Pathol. 2009; 62(11):1034-6. PMC: 2853932. DOI: 10.1136/jcp.2009.067801. View

Wikstrom P, Marusic J, Stattin P, Bergh A . Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients. Prostate. 2009; 69(8):799-809. DOI: 10.1002/pros.20927. View

Lee H, Hong Y, Etlioglu H, Cho Y, Pomella V, Van den Bosch B . Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer. Nat Genet. 2020; 52(6):594-603. DOI: 10.1038/s41588-020-0636-z. View

Han C, Liu T, Yin R . Biomarkers for cancer-associated fibroblasts. Biomark Res. 2020; 8(1):64. PMC: 7661188. DOI: 10.1186/s40364-020-00245-w. View

Bochet L, Lehuede C, Dauvillier S, Wang Y, Dirat B, Laurent V . Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res. 2013; 73(18):5657-68. DOI: 10.1158/0008-5472.CAN-13-0530. View

Higashino N, Koma Y, Hosono M, Takase N, Okamoto M, Kodaira H . Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of CCL2 and interleukin-6 in esophageal squamous cell carcinoma. Lab Invest. 2019; 99(6):777-792. DOI: 10.1038/s41374-018-0185-6. View

Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N . Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun. 2003; 309(1):232-40. DOI: 10.1016/s0006-291x(03)01544-4. View

Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart L . Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci U S A. 2001; 98(18):10356-61. PMC: 56965. DOI: 10.1073/pnas.171610498. View

10.

Tentaku A, Kurisu S, Sejima K, Nagao T, Takahashi A, Yonemura S . Proximal deposition of collagen IV by fibroblasts contributes to basement membrane formation by colon epithelial cells in vitro. FEBS J. 2022; 289(23):7466-7485. DOI: 10.1111/febs.16559. View

11.

Adegboyega P, Mifflin R, DiMari J, Saada J, Powell D . Immunohistochemical study of myofibroblasts in normal colonic mucosa, hyperplastic polyps, and adenomatous colorectal polyps. Arch Pathol Lab Med. 2002; 126(7):829-36. DOI: 10.5858/2002-126-0829-ISOMIN. View

12.

Kim K, Ahn A, Park H, Jang K, Moon W, Kang M . Clinical significance of p53 protein expression and TP53 variation status in colorectal cancer. BMC Cancer. 2022; 22(1):940. PMC: 9434900. DOI: 10.1186/s12885-022-10039-y. View

13.

Li A, Hasui K, Yonezawa S, Tanaka S, Sato E . Immunohistochemical analysis of pericryptal fibroblast sheath and proliferating epithelial cells in human colorectal adenomas and carcinomas with adenoma components. Pathol Int. 1999; 49(5):426-34. DOI: 10.1046/j.1440-1827.1999.00891.x. View

14.

Yao T, Tsuneyoshi M . Significance of pericryptal fibroblasts in colorectal epithelial tumors: a special reference to the histologic features and growth patterns. Hum Pathol. 1993; 24(5):525-33. DOI: 10.1016/0046-8177(93)90165-d. View

15.

Onfroy-Roy L, Hamel D, Malaquin L, Ferrand A . Colon Fibroblasts and Inflammation: Sparring Partners in Colorectal Cancer Initiation?. Cancers (Basel). 2021; 13(8). PMC: 8067599. DOI: 10.3390/cancers13081749. View

16.

Shindo K, Aishima S, Ohuchida K, Fujiwara K, Fujino M, Mizuuchi Y . Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas. Mol Cancer. 2013; 12(1):168. PMC: 3916072. DOI: 10.1186/1476-4598-12-168. View

17.

Prados A, Onder L, Cheng H, Morbe U, Lutge M, Gil-Cruz C . Fibroblastic reticular cell lineage convergence in Peyer's patches governs intestinal immunity. Nat Immunol. 2021; 22(4):510-519. PMC: 7610542. DOI: 10.1038/s41590-021-00894-5. View

18.

Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y . Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer. 2008; 123(5):1053-9. DOI: 10.1002/ijc.23611. View

19.

Fearon E, Vogelstein B . A genetic model for colorectal tumorigenesis. Cell. 1990; 61(5):759-67. DOI: 10.1016/0092-8674(90)90186-i. View

20.

Hewitt R, Powe D, Carter G, Turner D, Price J . Basement membrane collagen-IV synthesis in colorectal tumours. Int J Cancer. 1992; 51(4):530-6. DOI: 10.1002/ijc.2910510405. View