CN109541209B - Molecular model of esophageal squamous cell carcinoma microenvironment cell marker and application thereof - Google Patents
Molecular model of esophageal squamous cell carcinoma microenvironment cell marker and application thereof Download PDFInfo
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Abstract
The invention relates to a molecular model of esophageal squamous cell carcinoma microenvironment cell markers and application thereof, wherein the molecular model mainly comprises a-SMA+ (attack front)Fibroblast, CD163+ (interstitial substance)Macrophage, CD117+ (intrinsic layer)Mast cell, CD117+ (attack front)Mast cells; can be used for predicting the prognosis of patients with esophageal squamous carcinoma and grouping groups with sensitivity to adjuvant therapy. The kit mainly comprises an anti-CD 117 protein antibody, an anti-CD 163 protein antibody and an anti-a-SMA protein antibody. The 3 molecules adopted by the invention are combined with the histopathology characteristics to predict the prognosis of the patient, and the prognosis has higher prediction effect than that of single index detection, and simultaneously, the esophageal squamous carcinoma adjuvant therapy sensitive patient is also obviously distinguished, and the immunohistochemistry hypersensitivity type two-step method based on the invention is a mature and reliable method which can be widely used in primary hospitals. Compared with the international TNM staging, the method has higher prediction effect, is simpler and easier to implement, and has higher sensitivity and specificity.
Description
Technical Field
The invention relates to a method for detecting the expression condition of an esophageal squamous cell carcinoma patient specimen by combining a plurality of protein antibodies and histopathological characteristics and utilizing an immunohistochemical hypersensitivity type two-step method so as to predict the prognosis and adjuvant therapy sensitivity of the patient.
Background
Esophageal Squamous Cell Carcinoma (ESCC), abbreviated as Esophageal Squamous Cell Carcinoma, is a common upper gastrointestinal malignant tumor in China and is the fourth highest in the mortality rate of malignant tumors of Chinese. More than half of over 40 ten thousand new cases of esophageal squamous cell carcinoma occur in China every year, and China also is the first high-incidence country of esophageal squamous cell carcinoma recognized in the world. In the last 70 th century, general investigation of malignant tumors was conducted nationwide, and regions such as Hebei magnetic county, Henan Lin county, Shanxi Yang quan, Sichuan Yangtze, Guangdong Chaoshan and Jiangsu Huaian were determined to be the six high-incidence regions of esophageal squamous cell carcinoma in China.
The accurate prediction of the prognosis of the esophageal squamous carcinoma patient and the sensitivity of adjuvant therapy are of great significance to further clinical decision. However, there is no simple and effective method for predicting the prognosis of patients with esophageal squamous cell carcinoma more accurately except for the international TNM stage. However, the prognosis of the TNM staged prediction patient is complicated, the infiltration depth of the tumor, the number of metastatic lymph nodes, whether the tumor has distant metastasis or not and the like need to be accurately evaluated, and moreover, the international TNM staged formulation lacks a large amount of case data of esophageal squamous cell carcinoma of China, so that the applicability is poor when the prognosis of the patient in China is evaluated; the method is lack of available molecular markers in predicting the sensitivity of radiotherapy and chemotherapy.
The a-SMA marked tumor-associated fibroblasts are the main interstitial components of the microenvironment of various malignant solid tumors and play a key role in the process and treatment of tumors. Tumor-associated fibroblasts perform a variety of functions due to their different tissue sources that secrete different cytokines and extracellular matrices.
The CD163 marked macrophage is the most common inflammatory cell in the tumor microenvironment, plays a plurality of key roles in the tumor, has high plasticity and even influences the treatment of the tumor. It has been reported that IL-6 secretion by tumor-associated fibroblasts upregulates macrophage colony stimulating factor expression of monocytes, thereby differentiating monocytes into CD163+M2 type macrophage cell.
CD 117-labeled mast cells, a relatively controversial class of cells in the tumor microenvironment, often play different and even opposite roles in tumors.
Disclosure of Invention
In order to solve the problems, the invention provides a microenvironment cell marker molecular model of esophageal squamous cell carcinoma and application thereof.
A kit for predicting prognosis of an esophageal squamous carcinoma patient comprises an anti-CD 117 protein antibody, an anti-CD 163 protein antibody and an anti-a-SMA protein antibody.
The invention discovers that the cancer exists at the invasion front edge of esophageal squamous carcinomaA subgroup of tumor-associated fibroblasts do not directly influence the tumor cell EMT, but are associated with microenvironment remodeling and inflammatory cell activation and infiltration. CD163 in esophageal squamous carcinoma+Macrophage numbers were significantly correlated with poor prognosis in patients and closely correlated with tumor size, depth of tumor infiltration. Fibroblasts at the invasion front of esophageal squamous carcinoma are positively correlated with the number of macrophages. Mast cells of the esophageal squamous carcinoma lamina propria are associated with a good prognosis of the patient, while mast cells at the invasion front are closely associated with a poor prognosis of the patient. Whereas the fibroblast cells at the invasion front are inversely related to the number of mast cells.
Although CD117 protein, CD163 protein and a-SMA protein all have the ability to predict the prognosis of patients with esophageal squamous carcinoma, the tumor microenvironment as a complex whole has its cellular components dynamically changed and interacting to influence the development and treatment of tumor. Therefore, the 3 related molecules are combined with the characteristics of histology to predict the prognosis of the patient with esophageal squamous cell carcinoma, so that the prognosis has stronger judgment efficiency, even higher than the internationally recognized prediction capability of TNM stage, and the patient sensitive to the adjuvant therapy of esophageal squamous cell carcinoma can be distinguished.
The detection reagents of the kit are goat serum, 0.01M citrate repair liquid, 3% H2O2, a Polymer reinforcing agent, a Polymer, a DAB color reagent and a PBS solution respectively.
The kit for predicting the prognosis of the esophageal squamous cell carcinoma patient is applied to the preparation of a kit for jointly predicting the prognosis of the esophageal squamous cell carcinoma patient and grouping the esophageal squamous cell carcinoma patient to an auxiliary treatment sensitive group.
Wherein, the sample detected by the kit is a tissue wax block fixed by neutral formalin and embedded by paraffin.
Wherein, the used detection method is an immunohistochemical hypersensitivity type two-step method, which comprises the following steps: slicing neutral formalin-fixed and paraffin-embedded tissue wax blocks, dewaxing the slices until hydration, antigen repair, endogenous peroxidase inactivation and goat serum sealing, and respectively incubating with an anti-CD 117 protein antibody, an anti-CD 163 protein antibody and an anti-a-SMA protein antibody in a moisture retention box at 4 ℃ overnight; then respectively incubating with a Polymer intensifier and a Polymer, DAB developing and hematoxylin counterstaining cell nuclei; finally, after dehydration with alcohol and xylene clarification, the sections were mounted with neutral gum and scored on each stained section.
The anti-CD 117 protein antibody is used for marking the esophageal squamous carcinoma lamina propria and mast cells at the invasion front, the anti-CD 163 protein antibody is used for marking M2 type macrophages, the anti-a-SMA protein antibody is used for marking tumor-related fibroblasts, the Vectra multispectral section automatic analysis system is used for calculating the number of the mast cells at the lamina propria and the invasion front and the number of tumor stroma M2 type macrophages, and the expression value (staining intensity multiplied by positive area) of the a-SMA positive tumor-related fibroblasts at the invasion front is judged under a mirror. The cut-off values of high and low expression of the three proteins are determined by X-tile software, wherein the cut-off value of CD117 is 100, the cut-off value of CD163 is 600, and the cut-off value of a-SMA is 5 minutes.
A molecular model of microenvironment cell marker of esophageal squamous cell carcinoma mainly comprises a-SMA+ (attack front)Fibroblast, CD163+ (interstitial substance)Macrophage, CD117+ (intrinsic layer)Mast cell, CD117+ (attack front)Mast cells. .
The equation for constructing the molecular model is as follows: after each sample is respectively detected by using 3 protein antibodies, the calculation formula of 3 protein combined expression is that Y is alpha xA + beta xB + gamma beta x0C + delta xD, wherein alpha, beta, gamma and delta are coefficients and can be obtained by Cox regression, so that the formula is converted into that Y is 0.812 xA +1.788 xB + (-0.931) xC +0.967 xD; A. b, C, D are respectively the a-SMA of the specimen in this example+ (attack front)Fibroblast, CD163+ (interstitial substance)Macrophage, CD117+ (intrinsic layer)Mast cells and CD117+ (attack front)The expression status of mast cells, 0 for low expression and 1 for high expression; after calculating the Y value of each specimen, dividing patients with esophageal squamous carcinoma into high-, medium-, and low-risk groups (cut-off values are 1.80 and 2.76 respectively) according to X-tile software, namely, the high-risk group with the Y value larger than 2.76, and the medium-risk group with the Y value larger than or equal to 1.80 and smaller than or equal to 2.763Group, with Y values less than 1.80 are low risk groups.
The application of the molecular model of the esophageal squamous cell carcinoma microenvironment cell marker can be used for predicting prognosis of esophageal squamous cell carcinoma patients and grouping groups sensitive to adjuvant therapy.
When evaluating the information of individual esophageal squamous carcinoma patient prognosis and adjuvant therapy sensitivity, the Y value can be obtained by substituting the expression states corresponding to the immunohistochemical results of 3 proteins of the patient into a formula, and then the Y value is compared with the determined cut-off value. Obtaining the corresponding overall survival rates and tumor-free survival rates of 1 year, 3 years and 5 years, the survival conditions of the simple operation group and the operation and auxiliary treatment group, and obtaining the prognosis suggestions of different treatment modes.
Compared with the prior art, the 3 molecules adopted by the invention are combined with the histopathology characteristics to predict the prognosis of the patient, and the prognosis has higher prediction effect than that of single index detection, and simultaneously, the esophageal squamous carcinoma adjuvant therapy sensitive patient is also obviously distinguished, and the immunohistochemistry hypersensitivity type two-step method based on the invention is a mature and reliable method which can be widely used in primary hospitals. Compared with the international TNM staging, the method has higher prediction effect, is simpler and easier to implement, and has higher sensitivity and specificity.
Drawings
FIG. 1 is an attack front a-SMA+The Kaplan-Meier survival curve of the fibroblast in different expression populations (total survival rate: P0.002; tumor-free survival rate: P0.001).
FIG. 2 is interstitial CD163+Kaplan-Meier survival curve of macrophage in different expression populations (total survival rate: P)<0.001; tumor-free survival rate: p<0.001)。
FIG. 3 is a graph of the lamina propria and the attack front CD117+Kaplan-Meier survival curves of mast cells in different expression populations; lamina propria CD117+High expression of mast cells prolongs prognosis of esophageal squamous carcinoma patients, and invasion front CD117+Mast cells are associated with poor patient prognosis (lamina propria: overall survival: P)<0.001, tumor-free survival rate: p is 0.003; attack front: the total survival rate is as follows: p ═ 0.001, tumor-free survival: p ═ 0.011).
FIG. 4 is an attack front a-SMA+Fibroblast and mesenchymal CD163+Macrophage, CD117+Correlation of mast cells; attack front a-SMA+Fibroblast and mesenchymal CD163+Macrophages are positively correlated (R0.239 and P0.001), and invade a-SMA+Fibroblast and lamina propria, invasion front CD117+Mast cells are negatively associated (lamina propria: R ═ 0.359, P)<0.001; attack front: r ═ 0.207 and P ═ 0.003).
FIG. 5 is a Kaplan-Meier survival curve (total survival rate: P < 0.001; tumor-free survival rate: P <0.001) for this population judged by molecular modeling.
FIG. 6 is a ROC curve; the area under the ROC curve of the overall survival rate and the tumor-free survival rate of the molecular model is obviously higher than the stage of TNM.
FIG. 7 is a molecular model versus treatment; compared with the low-risk group and the medium-risk group, the high-risk group has obviously prolonged total survival and tumor-free survival of the esophageal squamous cell carcinoma patients through the operation and the adjuvant therapy.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer, in this embodiment, archival wax blocks of surgical specimens of 207 cases of esophageal squamous carcinoma patients in 2012-2014 were collected. The present invention will be described in further detail below with reference to the accompanying drawings.
The two-step method for immunohistochemical hypersensitivity type comprises the following steps:
after the sample is continuously sliced, dewaxed by dimethylbenzene and hydrated by gradient alcohol, the expression of the target protein is detected by a hypersensitive two-step method. The specific method comprises the following steps:
(1) the slices were antigen-repaired with 0.01M citrate repair solution, 3% H2O2Inactivating endogenous peroxidase, sealing goat serum, and respectively incubating with a-SMA, CD163 and CD117 antibodies at 4 ℃ overnight;
(2) after the sections are respectively incubated with the Polymer reinforcing agent and the Polymer, DAB color development is carried out;
(3) the slices are re-stained with hematoxylin, dehydrated by gradient alcohol, transparent by xylene and sealed by neutral gum;
(4) sections were washed with PBS solution after each step.
All immunostained sections were scored independently by 2 pathologists using blinding. a-SMA mainly evaluates positive fibroblasts at the invasion front, and the scoring method is expression intensity multiplied by positive area. The staining intensity was classified into 4 grades: 0, negative; 1, weak dyeing; 2, moderate dyeing; 3, strong dyeing. The percentage of positive cells was classified as grade 5: 0, 0-5%; 1, 6-25%; 2, 26-50%; 3, 51-75%; 4, more than or equal to 76 percent. The total fraction of each specimen is obtained by multiplying the staining intensity of the tumor cells and the positive percentage of the tumor cells, and the range is 0-12. CD163+Macrophages and CD117+Mast cell numbers were calculated by the Vectra multispectral section automated analysis system. According to the operation specification of a standard Vectra multispectral slice automatic analysis system, firstly, a tissue slice is automatically scanned under a 40-time mirror, then, a picture is collected under a 200-time mirror, and a CD163 is automatically identified through the Vectra system+Macrophages and CD117+Mast cells, then the top 20 pictures with the highest number of positive cells were summed. For the convenience of statistics, all cases were divided into low-expression and high-expression 2 groups, 0 for low-expression group and 1 for high-expression group, and cut-off values thereof were determined according to X-tile software. a-SMA: 0-5 is divided into a low expression group, and 6-12 is divided into a high expression group; CD163+Macrophage number: 0-600 is a low expression group, and more than 600 is a high expression group; CD117+Mast cell number: 0-100 is a low expression group, and more than 100 is a high expression group.
Attack front a-SMA+Fibroblast, mesenchymal CD163+Macrophage, lamina propria CD117+Mast cell and invasion front CD117+The equations for the mast cells combined to construct the molecular model are as follows:
y ═ α × a + β × B + γ β × 0C + δ × D, where α, β, γ, δ are coefficients, can be obtained by Cox regression, so that this formula translates to Y ═ 0.812 × a +1.788 × B + (-0.931) × C +0.967 × D; A. b, C, D are respectively the a-SMA of the specimen in this example+(invasion front) fibroblasts, CD163+(interstitial) macrophages, CD117+(lamina propria) mast cells and CD117+(invasion front) expression status of mast cells, 0 for low expression and 1 for high expression; after calculating the Y value of each specimen, patients with esophageal cancer were classified into high-, medium-, and low-risk groups (cut-off values of 1.80 and 2.76, respectively) according to X-tile software, i.e., those with a Y value of greater than 2.76 were high-risk groups, those with a Y value of 1.80 or greater and 2.763 or less were medium-risk groups, and those with a Y value of less than 1.80 were low-risk groups. Then, single-factor multi-factor analysis and ROC analysis are carried out.
Statistical processing of data:
data were processed using SPSS 19.0 statistical software. The relationship between the expression of each interstitial component and the survival time of the patient was analyzed using Kaplan-Meier survival; predicting independent risk factors affecting patient prognosis using a Cox proportional hazards regression model; the relationship between the expression of each interstitial component and the clinical pathological parameters is analyzed by using Fisher's exact test; the effectiveness of each component in predicting the prognosis of the esophageal squamous carcinoma patient uses the ROC curve; p <0.05 was considered statistically significant.
The results show that:
a-SMA+(invasion front) fibroblasts, CD163+(interstitial) macrophages, CD117+(lamina propria) mast cells, CD117+The survival relationships of the (invasion front) mast cell and molecular models with esophageal squamous carcinoma patients are shown in FIGS. 1-3. Attack front a-SMA as shown in FIG. 1+High expression of fibroblasts shortens the overall survival and tumor-free survival of patients with esophageal squamous cell carcinoma. FIG. 2 survival analysis found CD163+(interstitial) macrophages are associated with poor prognosis in patients with esophageal squamous carcinoma. The results in FIG. 3 show that the lamina propria CD117+Mastocytosis significantly prolongs the overall survival and tumor-free survival of patients with esophageal squamous carcinoma, while the invasion front is CD117+The total survival and tumor-free survival of the patients with the high-expression mast cell esophageal squamous carcinoma are obviously reduced in the lower-expression group.
As shown in FIG. 4, correlation analysis revealed that the attack front a-SMA+Expression of fibroblasts and CD163+The number of (interstitial) macrophages is proportional to the lamina propria CD117+Mast cell, invasion front CD117+Mast cells are inversely related.
Fig. 5 survival analysis found that the molecular model high-risk group significantly shortened the overall survival and tumor-free survival of patients with esophageal squamous cell carcinoma compared to the low-risk group.
FIG. 6ROC analysis shows that the prediction efficiency of the molecular model on the total survival and tumor-free survival of the esophageal squamous carcinoma patients is obviously higher than that of Ptnm-stage.
Fig. 7 shows that the molecular model high-risk group significantly benefits the adjuvant therapy, and the total survival rate of the high-risk group for the surgical patients in 1 year and the tumor-free survival rate are 12.5% and 0% respectively; while the 1-year overall survival rate and tumor-free survival rate of the patients treated by the surgery and adjuvant therapy in the high-risk group are 66.7% and 37.5%, respectively. The molecular model high-risk group of esophageal squamous carcinoma patients obviously benefits the adjuvant therapy.
a-SMA+(invasion front) fibroblasts, CD163+(interstitial) macrophages, CD117+(lamina propria) mast cells, CD117+The relationship between the expression of mast cells (invasion front) and the clinical pathological parameters of esophageal squamous carcinoma patients is shown in Table 1: table 1 results show the attack front a-SMA+Fibroblasts and CD163+(interstitial) macrophages are associated with tumor size, depth of infiltration; CD117+The (lamina propria) mast cells are associated with tumor size, depth of infiltration, lymph node metastasis and clinical staging.
TABLE 1 relationship between markers and clinical pathological parameters of patients with esophageal squamous cell carcinoma
*Fisher's Exact Test；P value<0.05was considered significant.
a a-SMA(Invasive front of tumor),low,≤4scores；high,>4scores
b CD163(Stroma),low,≤600cells；high,>600cells
c CD117(Lamina propria),low,≤100cells；high,>100cells
d CD117(Invasive front of tumor),low,≤100cells；high,>100cells
The Cox risk regression model predicts the independent risk factors for the patient as follows:
the analysis results in the table 2 show that the molecular model has stronger prognosis prediction capability of esophageal squamous cell carcinoma and is an independent prognostic factor.
TABLE 2 univariate and multivariate analysis results of the overall survival rate and tumor-free survival rate of patients with esophageal squamous cell carcinoma
Note: multifactor analysis, Cox proportional hazards regression model. Prognostic significance of single factor analysis variables.
When evaluating the individual esophageal squamous carcinoma patient prognosis and adjuvant therapy sensitivity information, the Y value can be obtained by substituting the expression states corresponding to the immunohistochemical results of 3 proteins of the patient into the formula, and then comparing with the determined cut-off value, and the survival conditions corresponding to each risk group are shown in Table 3:
TABLE 3207 survival status of various risk groups of molecular models of esophageal squamous carcinoma patients
Obtaining the corresponding overall survival rates and tumor-free survival rates of 1 year, 3 years and 5 years, the survival conditions of the simple operation group and the operation and auxiliary treatment group, and obtaining the prognosis suggestions of different treatment modes.
Molecular model and comparison of predicted potency of each individual molecular marker, pTNM-stage
From Table 4, it was found that the molecular model predicted better than the single index, pTNM-stage.
TABLE 4 ROC analysis results
Claims (9)
1. The application of the anti-CD 117 protein antibody, the anti-CD 163 protein antibody and the anti-a-SMA protein antibody in preparing a kit for predicting the prognosis of an esophageal squamous carcinoma patient.
2. The use of claim 1, wherein the kit further comprises goat serum, 0.01M citrate repair solution, 3% H2O2Polymer reinforcing agent, Polymer, DAB color reagent and PBS solution.
3. The application of the anti-CD 117 protein antibody, the anti-CD 163 protein antibody and the anti-a-SMA protein antibody in preparing a group kit for jointly predicting prognosis of esophageal squamous carcinoma patients and grouping sensitive groups for adjuvant therapy.
4. The use of claim 3, wherein the specimen to be tested is neutral formalin fixed paraffin embedded tissue wax block.
5. The use according to claim 3, characterized in that the detection method used is an immunohistochemical hypersensitivity type two-step method, comprising the following specific steps: slicing neutral formalin-fixed and paraffin-embedded tissue wax blocks, dewaxing the slices until hydration, antigen repair, endogenous peroxidase inactivation and goat serum sealing, and respectively incubating with an anti-CD 117 protein antibody, an anti-CD 163 protein antibody and an anti-a-SMA protein antibody in a moisture retention box at 4 ℃ overnight; then, after respectively incubating with the Polymer intensifier and the Polymer, DAB color development and hematoxylin counterstain cell nucleus; finally, after dehydration with alcohol and xylene clarification, the sections were mounted with neutral gum and scored on each stained section.
6. The use of claim 5, wherein the anti-CD 117 protein antibody is labeled with esophageal squamous carcinoma lamina propria and mast cells at the invasion front, the anti-CD 163 protein antibody is labeled with macrophages of type M2, the anti-a-SMA protein antibody is labeled with tumor-associated fibroblasts, the Vectra multispectral slice automatic analysis system is used for calculating the number of mast cells at the lamina propria, the invasion front and the number of macrophages of type M2 tumor stroma, and the expression value of a-SMA positive tumor-associated fibroblasts at the invasion front is discriminated under the mirror; cut-off values of high and low expression of CD117 protein, CD163 protein and a-SMA protein are determined by X-tile software.
7. A molecular model of microenvironment cell markers of esophageal squamous cell carcinoma is characterized in that the formula for constructing the molecular model is as follows: y =0.812 × a +1.788 × B + (-0.931) × C +0.967 × D; wherein A, B, C, D are each a-SMA+ Attack frontFibroblast, CD163+ Matrix of ChinaMacrophage, CD117+ Intrinsic layerMast cells and CD117+ Attack frontThe expression status of mast cells, 0 for low expression and 1 for high expression; after calculating the Y value, the patients with esophageal squamous carcinoma are classified into high-, medium-, and low-risk groups according to X-tile software, namely a high-risk group with a Y value of more than 2.76, a middle-risk group with a Y value of more than or equal to 1.80 and less than or equal to 2.763, and a low-risk group with a Y value of less than 1.80.
8. The application of the molecular model of the esophageal squamous cell carcinoma microenvironment marker is characterized in that the molecular model can be used for predicting the prognosis and grouping of groups sensitive to adjuvant therapy of esophageal squamous cell carcinoma patients.
9. The use of claim 8, wherein when evaluating the prognosis and sensitivity of adjuvant therapy for an individual patient with esophageal squamous carcinoma, the Y value can be obtained by substituting the expression status corresponding to the immunohistochemical result of 3 proteins of the patient into the formula, and then comparing the Y value with the cut-off value.
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