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. 2018 Feb 1:414:153-165.
doi: 10.1016/j.canlet.2017.11.011. Epub 2017 Nov 15.

Prostate cancer health disparities: An immuno-biological perspective

Sanjay Kumar  1 , Rajesh Singh  2 , Shalie Malik  3 , Upender Manne  4 , Manoj Mishra  5
Affiliations

Prostate cancer health disparities: An immuno-biological perspective

Sanjay Kumar et al. Cancer Lett. .

Abstract

Prostate cancer (PCa) is the most commonly diagnosed malignancy in males, and, in the United States, is the second leading cause of cancer-related death for men older than 40 years. There is a higher incidence of PCa for African Americans (AAs) than for European-Americans (EAs). Investigations related to the incidence of PCa-related health disparities for AAs suggest that there are differences in the genetic makeup of these populations. Other differences are environmentally induced (e.g., diet and lifestyle), and the exposures are different. Men who immigrate from Eastern to Western countries have a higher risk of PCa than men in their native countries. However, the number of immigrants developing PCa is still lower than that of men in Western countries, suggesting that genetic factors are involved in the development of PCa. Altered genetic polymorphisms are associated with PCa progression. Androgens and the androgen receptor (AR) are involved in the development and progression of PCa. For populations with diverse racial/ethnic backgrounds, differences in lifestyle, diet, and biology, including genetic mutations/polymorphisms and levels of androgens and AR, are risk factors for PCa. Here, we provide an immuno-biological perspective on PCa in relation to racial/ethnic disparities and identify factors associated with the disproportionate incidence of PCa and its clinical outcomes.

Keywords: Health disparity; Immunotherapy; Prostate cancer.

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Conflict of interest statement

18. Conflict of interest: None

Figures

Fig. 1
Fig. 1
A schematic presentation of different pathways involved in PCa disparity.1. In the cytoplasm, testosterone is reduced to dihydrotestosterone (DHT) in the presence of 5α-reductase and binds to the androgen receptor (AR). The DHT/AR complex migrates to the nucleus and binds to androgen responsive elements (ARE) that further stimulates the activation of gene transcription. 2. After ligand interaction, receptor tyrosine kinase such as EGFR/PDGF/IGF stimulates its phosphorylation and subsequently actives PI3K and Akt pathway which further leads to the activation and migration of mTOR to the nucleus. In the nucleus, activated mTOR induces initiation of gene transcription, which results in proliferation, survival, and angiogenesis. 3. Binding of cytokines such as interleukin 6 (IL-6) to its receptor initiates several cellular events including activation of Janus kinase (JAK)/signal transducer and activating of transcription 3 (STAT3). Activated STAT3 forms homodimers that move to the nucleus and stimulates gene transcription. In brief, activation of; 1. androgen receptor, 2. receptor tyrosine kinase, and 3. Cytokine, induced downstream activation of responsive genes which are critical for PCa cells existence.
Fig. 2
Fig. 2
A schematic presentation of the factors associated with PCa disparity. Multiple factors such as genetic polymorphism, gene mutations, overexpression/suppression of microRNAs, epigenetic alteration, and alteration in molecular cell signaling pathways can play a significant role in PCa racial disparity. Defective function in polymorphism associated factors (DG8S737, CYP3A4*1B, CYP3A5*1, CYP3A43*3, Arg462Gln)/Gene mutation (EPHB2, K1019X, BRACA2, COI) may lead to PCa racial disparity. Similarly, overexpression/downregulation of miRNAs (miR-26a, 30c, 30-C1, let7C, 1b-1 and paired miRNAs (miR-133a/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-45/ITPR2), alteration in cytokines (IL-1β, IL-6, IL-8, TGF-β, etc.), androgen hormone signaling, and epigenetic factors (APC, RARβB, SPARC, EDNRB, CD44, RASSF1, CAV1, ANXA2, CDH1, ANKX2, TIMP3, GSTP1, AR, ARβ2) may results in PCa disparity.
Fig. 3
Fig. 3
Diagrammatic presentation of the role of effector function of NKT cells in immune regulation. Interaction of NKT cells with T cells, macrophages, and dendritic cells results in secretion of several cytokines such as IL-4, IL-10, IL-13, IL-21, IFN-γ which require for the activation of these cells. After activation, T cells divide frequently and secrete cytokines necessary for active immune response. Moreover, B cell interaction with NKT cells resulted in activation of B cells while NKT cell interaction with neutrophil suppresses its effector function.
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