Expression differences between African American and Caucasian prostate cancer tissue reveals that stroma is the site of aggressive changes

Abstract

In prostate cancer, race/ethnicity is the highest risk factor after adjusting for age. African Americans have more aggressive tumors at every clinical stage of the disease, resulting in poorer prognosis and increased mortality. A major barrier to identifying crucial gene activity differences is heterogeneity, including tissue composition variation intrinsic to the histology of prostate cancer. We hypothesized differences in gene expression in specific tissue types would reveal mechanisms involved in the racial disparities of prostate cancer. We examined seventeen pairs of arrays for African Americans and Caucasians that were formed by closely matching the samples based on the known tissue type composition of the tumors. Using pair wise T-test we found significantly altered gene expression between African Americans and Caucasians. Independently, we performed multiple linear regression analyses to associate gene expression with race considering variation in percent tumor and stroma tissue. The majority of differentially expressed genes were associated with tumor-adjacent stroma rather than tumor tissue. Extracellular matrix, Integrin family and signaling mediators of the epithelial-to-mesenchymal transition pathways were all down regulated in stroma of African Americans. Using MetaCore (GeneGo Inc.) analysis, we observed that 35% of significant (p < 10-3) pathways identified EMT and 25% identified immune response pathways especially for Interleukins -2, -4, -5, -6, -7, -10, -13, -15 and -22 as the major changes. Our studies reveal that altered immune and EMT processes in tumor-adjacent stroma may be responsible for the aggressive nature of prostate cancer in African Americans.

Reclassification Rates Are Higher Among African American Men Than Caucasians on Active Surveillance

“…The biological mechanisms underlying PCa disparities in AA are largely unknown, though some investigators have begun to shed light on certain molecular differences. 18–21 Studies analyzing the molecular basis of tumorigenesis in the anterior aspect of the prostate may reveal insights into racial disparities in PCa, which are also underway.…”

AGE Metabolites: A Biomarker Linked to Cancer Disparity?

“…The significance of AGE accumulation as an inflammatory mediator that contributes to the excessive risk and mortality among African-American men may arise from the fact that poor diet and a lack of exercise are lifestyle factors particularly prevalent within African American communities who are also known to have and increased burden of inflammation associated chronic disease. Significantly, differential cytokine expression associated with an increased immune response was found to be a predominant pathway increased in African American prostate cancer patients (1). A similar race specific increase in immune response gene copy number and gene expression was also observed in matched radical prostatectomy tissues (24) and in Gleason 6 prostate tumors (4).…”

“…African American prostate cancer patients are more likely to develop aggressive prostate cancer and die of their disease than their European American counterparts (1-4). Poor diet and a lack of physical activity are potential risk factors for prostate cancer.…”

“…In particular, established factors such as low income, poor diet and a sedentary lifestyle may confer molecular effects that alter cell signaling and gene expression patterns, including expression of non-coding RNAs, and effect chromosomal stability and therefore accelerate tumor development and progression (1-4). In other words our lifestyle choices may have profound effects on tumor development and progression which may contribute to health disparity outcomes such as the earlier development of cancer or the progression to more aggressive disease.…”

Racial disparities in prostate cancer a molecular perspective

“…Furthermore, bioinformatics analysis revealed that most of the differentially-expressed genes, including those encoding for autocrine mobility factor receptor (AMFR), chemokine receptor 4 (CXCR4), and matrix metalloproteinase 9 (MMP9), were associated with immune response, stress response, cytokine signaling, chemotaxis, and inflammation or tumor-immunobiology (59). In another microarray-based study, it was shown that genes associated with immune-related pathways, including IL1B , IL6 , and IL8 , were overexpressed in prostate cancer tissues from AA men compared to those from EA men (60). In addition, many stroma-associated genes were also found to be differentially-expressed in AA tumors relative to EA tumors.…”