J Korean Med Sci.  2013 Sep;28(9):1293-1301. 10.3346/jkms.2013.28.9.1293.

Podoplanin, alpha-Smooth Muscle Actin or S100A4 Expressing Cancer-Associated Fibroblasts Are Associated with Different Prognosis in Colorectal Cancers

• Choi SY
• Sung R
• Lee SJ
• Lee TG
• Kim N
• Yoon SM
• Lee EJ
• Chae HB
• Youn SJ
• Park SM

• KMID: 1793043
• DOI: http://doi.org/10.3346/jkms.2013.28.9.1293

Abstract

The interactions between the tumor microenvironment and tumor cells determine the behavior of the primary tumors. Whether cancer-associated fibroblasts (CAF) have a tumor progressive or a protective role likely depends on the type of tumor cells and the CAF subpopulation. In the present study, we analyzed the prognostic significance of CAF subpopulations in colorectal cancer (CRC). CAF phenotypes were analyzed in 302 CRC patients by using antibodies against podoplanin (PDPN), alpha-smooth muscle actin (alpha-SMA), and S100A4. The relationship between the CAF phenotypes and 11 clinicopathological parameters were evaluated and their prognostic significance was analyzed from the disease-free and overall survival times. We observed that at the tumor invasive front, PDPN CAFs were present in 40% of the cases, and S100A4 or alpha-SMA CAFs were detected in all the cases. PDPN/S100A4 and alpha-SMA/S100A4 dual-stained CAFs were observed in 10% and 40% of the cases, respectively. The PDPN+ CAFs were associated with 6 favorable clinicopathological parameters and prolonged disease-free survival time. The PDPN-/alpha-SMA(high) CAFs were associated with 6 aggressive clinicopathological parameters and tended to exhibit shorter disease-free survival time. On the other hand, the PDPN-/S100A4(high) CAFs were associated with 2 tumor progression parameters, but not with disease prognosis. The PDPN+ CAF phenotype is distinct from the alpha-SMA or S100A4 CAFs in that it is associated with less aggressive tumors and a favorable prognosis, whereas the PDPN-/alpha-SMA(high) or PDPN-/S100A4(high) CAFs are associated with tumor progression in CRC. These findings suggest that CAFs can be a useful prognostic biomarker or potential targets of anti-cancer therapy in CRC.

Keyword

Cancer-Associated Fibroblast; Podoplanin; alpha-Smooth Muscle Actin; S100A4; Colorectal Neoplasms

MeSH Terms

Actins/immunology/*metabolism
Adult
Aged
Aged, 80 and over
Antibodies/immunology
Carcinoembryonic Antigen/blood
Colorectal Neoplasms/*diagnosis/mortality/pathology
Disease-Free Survival
Female
Fibroblasts/cytology/metabolism
Humans
Immunohistochemistry
Lymphatic Metastasis
Male
Membrane Glycoproteins/immunology/*metabolism
Middle Aged
Neoplasm Staging
Phenotype
Prognosis
S100 Proteins/immunology/*metabolism
Tumor Markers, Biological/metabolism
Actins
Antibodies
Carcinoembryonic Antigen
Membrane Glycoproteins
S100 Proteins
Tumor Markers, Biological

Figure

• 

  Fig. 1 Immunohistochemistry for different markers of cancer associated fibroblasts (CAFs) in colorectal carcinomas (×400). (A) Podoplanin (PDPN) expression was not observed in the normal stromal cells, except for the lymphatic vessels (arrow). (B) α-SMA expression in smooth muscle cells (arrow) and vessels (empty arrow). (C) S100A4 expression in inflammatory cells (arrow). (D) α-SMA-positive myofibroblasts appeared as spindle shaped stromal cells with long cytoplasmic extensions. (E) S100A4-positive CAF (arrow) in the tumor stroma surrounding the carcinoma cells. (F) Dual stained CAFs with PDPN (empty arrow) and S100A4 (arrow). (G) Dual stained CAFs with α-SMA (empty arrow) and S100A (arrow).

• 

  Fig. 2 Disease-free survival curves based on the CAF subpopulation, with PDPN+ at the tumor center (A), PDPN+ at the invasive front (B), PDPN-/α-SMAhigh (C), and PDPN-/S100A4high (D) in colorectal cancers.

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