CD73 as a novel prognostic biomarker for human colorectal cancer
2
Journal of Surgical Oncology LETTER TO THE EDITOR CD73 as a Novel Prognostic Biomarker for Human Colorectal Cancer NAN LIU, MD, 1 XUE-DONG FANG, MD, PhD, 1 * AND QUO VADIS, MD 2 1 Department of General Surgery, Second Hospital of Jilin University, Changchun, China 2 Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden We would like to congratulate Wu et al. [1] on their novel find- ings that high expression of CD73 is an independent biomarker for predicting the poor survival of patients with colorectal cancer (CRC). The study was well designed and conducted, promising that CD73 may serve as a useful biomarker additive to the American Joint Committee on Cancer (AJCC) TNM staging system for patients with CRC. Without placing too much emphasis on the merits of their study, we wonder if the authors have considered other confounding factors when interpreting their results. CD73 (ecto-5 0 -nucleotidase) is an ectoenzyme, which produces adenosine from adenosine monophosphate precursor by enzymatic dephosphorylation [2]. Although originally defined as a lymphocyte differentiation antigen, CD73 has been identified as a cosignaling molecule on T cells and as an adhesion molecule required for lym- phocytes binding to endothelium [3]. Expression of CD73 has been found upregulated in multiple cancerous tissues [4,5]. Studies have shown that CD73 on tumor cells could markedly inhibit the prolifer- ation of human CD4 þ T cells as well as cytotoxic T-cell priming and natural killer (NK) cell cytotoxicity, which is classified as a novel mechanism of tumor-induced immune suppression [6]. In addition to tumor cells, suppressive immune subsets such as regulatory T cells (Tregs), B cells, myeloid-derived suppressor cells and endothelial cells are CD73 positive and the levels of expression on lymphocytes are increased with maturation [7,8]. In this study, the expression of CD73 was detected by both Western blotting and immunohistochemistry. For Western blotting analysis, one drawback is that the detected expression of CD73 in tissue protein extractions can not be localized, since immune cells and others can also express CD73 [7,8]. For immunohistochemistry, only single staining was used; thus the same question stands. Never- theless, one may be interested to know if there is any difference of CD73 expression with reference to the histopathological type of CRC. Besides, ‘‘Expression dynamics’’ was mentioned several times by the authors. Regretfully, a description of expression dynamics of CD73, that is, a diagram showing the expression level of CD73 in serial AJCC stages (I–IV) was not presented. In Figure 3B, the optimal cutpoint for CD73 expression deter- mined by X-tile analysis of the training cohort was applied to the validation cohort and reached statistical significance in the Kaplan– Meier survival analysis [1]. Although survival time differed signifi- cantly between the high and low expression groups, confounding factors such as the AJCC stage were not adjusted. In Figure 4 [1], similarly, we wonder whether duration of disease and age may great- ly influence the Kaplan–Meier curve. We especially agree on the statement that CD73 expression can be used to identify patients who are more likely to progress and recur, and to receive more aggressive treatment. However, existing data indicate that the specificity of CD73 in cancers is low [9]. Before the sensitivity of CD73 expression in CRC and other cancers are clarified, it seems more promising to combine CD73 with other prognostic factors to predict the outcome of CRC. As reported in the article, the training cohort demonstrated that CD73 expression was significantly correlated with preoperative serum CEA levels, tumor differentiation and AJCC stage, etc. We thus wonder if the authors tried to use combined ways, for example, serum CEA level and CD73 expression, to predict the prognosis of CRC. It has been noted that important data on postoperative chemo- therapies were missing in the present study. This may confound the prediction of prognosis. It has been recently reported that CD73 can mediate resistance to chemotherapy in leukemia [10]. For further studies, one may be interested to know whether chemotherapy may differentially influence the survival of patients with different levels of CD73 expression. It would be more meaningful to find that patients with CRC and high CD73 expression require anti-CD73 therapies. In summary, CD73 is a novel prognostic biomarker for human CRC. Further studies are warranted to investigate its diagnostic and prognostic values as well as the potentials of CD73 blockade in cancer treatment. REFERENCES 1. Wu XR, He XS, Chen YF, et al.: High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J Surg Oncol 2012; DOI: 10.1002/jso.23056 [Epub ahead of print]. 2. Zhang B: CD73: A novel target for cancer immunotherapy. Cancer Res 2010;70:6407–6411. 3. Resta R, Thompson LF: T cell signalling through CD73. Cell Signal 1997;9:131–139. 4. Eroglu A, Canbolat O, Demirci S, et al.: Activities of adenosine deaminase and 50-nucleotidase in cancerous and noncancerous human colorectal tissues. Med Oncol 2000;17:319–324. Conflicts of interest: None to declare. Post script: All authors listed have proof-read and agreed to the publica- tion of this letters. *Correspondence to: Xue-Dong Fang, MD, PhD, Department of General Surgery, Second Hospital of Jilin University, Jilin University, 130000 Changchun, China. Fax: 86-431-88796114. E-mail: [email protected] Received 21 April 2012; Accepted 25 April 2012 DOI 10.1002/jso.23159 Published online in Wiley Online Library (wileyonlinelibrary.com). ß 2012 Wiley Periodicals, Inc.
Transcript of CD73 as a novel prognostic biomarker for human colorectal cancer
Journal of Surgical Oncology
LETTER TO THE EDITOR
CD73 as a Novel Prognostic Biomarker for Human Colorectal Cancer
NAN LIU, MD,1 XUE-DONG FANG, MD, PhD,1* AND QUO VADIS, MD2
1Department of General Surgery, Second Hospital of Jilin University, Changchun, China2Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
We would like to congratulate Wu et al. [1] on their novel find-
ings that high expression of CD73 is an independent biomarker
for predicting the poor survival of patients with colorectal cancer
(CRC). The study was well designed and conducted, promising that
CD73 may serve as a useful biomarker additive to the American
Joint Committee on Cancer (AJCC) TNM staging system for patients
with CRC. Without placing too much emphasis on the merits of their
study, we wonder if the authors have considered other confounding
factors when interpreting their results.
CD73 (ecto-50-nucleotidase) is an ectoenzyme, which produces
adenosine from adenosine monophosphate precursor by enzymatic
dephosphorylation [2]. Although originally defined as a lymphocyte
differentiation antigen, CD73 has been identified as a cosignaling
molecule on T cells and as an adhesion molecule required for lym-
phocytes binding to endothelium [3]. Expression of CD73 has been
found upregulated in multiple cancerous tissues [4,5]. Studies have
shown that CD73 on tumor cells could markedly inhibit the prolifer-
ation of human CD4þ T cells as well as cytotoxic T-cell priming and
natural killer (NK) cell cytotoxicity, which is classified as a novel
mechanism of tumor-induced immune suppression [6]. In addition to
tumor cells, suppressive immune subsets such as regulatory T cells
(Tregs), B cells, myeloid-derived suppressor cells and endothelial
cells are CD73 positive and the levels of expression on lymphocytes
are increased with maturation [7,8].
In this study, the expression of CD73 was detected by both
Western blotting and immunohistochemistry. For Western blotting
analysis, one drawback is that the detected expression of CD73 in
tissue protein extractions can not be localized, since immune cells
and others can also express CD73 [7,8]. For immunohistochemistry,
only single staining was used; thus the same question stands. Never-
theless, one may be interested to know if there is any difference
of CD73 expression with reference to the histopathological type of
CRC. Besides, ‘‘Expression dynamics’’ was mentioned several times
by the authors. Regretfully, a description of expression dynamics of
CD73, that is, a diagram showing the expression level of CD73 in
serial AJCC stages (I–IV) was not presented.
In Figure 3B, the optimal cutpoint for CD73 expression deter-
mined by X-tile analysis of the training cohort was applied to the
validation cohort and reached statistical significance in the Kaplan–
Meier survival analysis [1]. Although survival time differed signifi-
cantly between the high and low expression groups, confounding
factors such as the AJCC stage were not adjusted. In Figure 4 [1],
similarly, we wonder whether duration of disease and age may great-
ly influence the Kaplan–Meier curve.
We especially agree on the statement that CD73 expression can
be used to identify patients who are more likely to progress and
recur, and to receive more aggressive treatment. However, existing
data indicate that the specificity of CD73 in cancers is low [9].
Before the sensitivity of CD73 expression in CRC and other cancers
are clarified, it seems more promising to combine CD73 with other
prognostic factors to predict the outcome of CRC. As reported in the
article, the training cohort demonstrated that CD73 expression was
significantly correlated with preoperative serum CEA levels, tumor
differentiation and AJCC stage, etc. We thus wonder if the authors
tried to use combined ways, for example, serum CEA level and
CD73 expression, to predict the prognosis of CRC.
It has been noted that important data on postoperative chemo-
therapies were missing in the present study. This may confound the
prediction of prognosis. It has been recently reported that CD73 can
mediate resistance to chemotherapy in leukemia [10]. For further
studies, one may be interested to know whether chemotherapy may
differentially influence the survival of patients with different levels
of CD73 expression. It would be more meaningful to find that
patients with CRC and high CD73 expression require anti-CD73
therapies.
In summary, CD73 is a novel prognostic biomarker for human
CRC. Further studies are warranted to investigate its diagnostic
and prognostic values as well as the potentials of CD73 blockade in
cancer treatment.
REFERENCES
1. Wu XR, He XS, Chen YF, et al.: High expression of CD73 as apoor prognostic biomarker in human colorectal cancer. J SurgOncol 2012; DOI: 10.1002/jso.23056 [Epub ahead of print].
2. Zhang B: CD73: A novel target for cancer immunotherapy.Cancer Res 2010;70:6407–6411.
3. Resta R, Thompson LF: T cell signalling through CD73. CellSignal 1997;9:131–139.
4. Eroglu A, Canbolat O, Demirci S, et al.: Activities of adenosinedeaminase and 50-nucleotidase in cancerous and noncanceroushuman colorectal tissues. Med Oncol 2000;17:319–324.
Conflicts of interest: None to declare.
Post script: All authors listed have proof-read and agreed to the publica-tion of this letters.
*Correspondence to: Xue-Dong Fang, MD, PhD, Department of GeneralSurgery, Second Hospital of Jilin University, Jilin University, 130000Changchun, China. Fax: 86-431-88796114.E-mail: [email protected]
Received 21 April 2012; Accepted 25 April 2012
DOI 10.1002/jso.23159
Published online in Wiley Online Library(wileyonlinelibrary.com).
� 2012 Wiley Periodicals, Inc.
5. Kondo T, Nakazawa T, Murata SI, et al.: Expression of CD73and its ecto-50-nucleotidase activity are elevated in papillarythyroid carcinomas. Histopathology 2006;48:612–614.
6. Jin D, Fan J, Wang L, et al.: CD73 on tumor cells impairs anti-tumor T-cell responses: A novel mechanism of tumor-inducedimmune suppression. Cancer Res 2010;70:2245–2255.
7. Beavis PA, Stagg J, Darcy PK, et al.: CD73: A potent suppres-sor of antitumor immune responses. Trends Immunol 2012;DOI: 10.1016/j.bbr.2011.03.031 [Epub ahead of print].
8. Yamashita Y, Hooker SW, Jiang H, et al.: CD73 expression andfyn-dependent signaling on murine lymphocytes. Eur J Immunol1998;28:2981–2990.
9. Stagg J, Smyth MJ: Extracellular adenosine triphosphate andadenosine in cancer. Oncogene. 2010;29:5346–5358.
10. Serra S, Horenstein AL, Vaisitti T, et al.: CD73-generated extra-cellular adenosine in chronic lymphocytic leukemia createslocal conditions counteracting drug-induced cell death. Blood2011;118:6141–6152.
2 Liu et al.
Journal of Surgical Oncology
