Urologic Oncology: Seminars and Original Investigations
Review articleIntratumor heterogeneity in prostate cancer
Introduction
Cancer, the uncontrolled division and spread (metastasis) of abnormal cells within the body, has existed in humans and animal species throughout history [1]. Bone tumors, as well as cancers of the head and neck, were discovered in ancient Egyptian mummies as well as recorded in the Edwin Smith Papyrus (an ancient Egyptian manuscript on trauma surgery) dating back to 3,000 BCE. The document detailed 8 cases of breast malignancies, which were cauterized by a device called a fire drill [2]. Over time, we have made tremendous progress in understanding and treating cancer however, therapeutic success has been impeded by disease recurrence, even when cancer is at undetectable levels. Throughout the decades the practice of studying cancer has evolved into a field which now observes the behavioral patterns of cancer cells at the individual level, a concept known as intra-tumor heterogeneity (ITH), which seeks to understand the distinct genetic and phenotypic profiles contained within individual cancer cells.
Traditionally we have viewed the development of cancer in a linear fashion, where aberrations in oncogenes and tumor suppressors accumulate to a point where the cells(s) are fully malignant. Currently we have a limited understanding of the number of driver changes needed for tumor initiation and progression, and the effect(s) of the tumor microenvironment on these events. It is believed that in most solid cancers, between 2 and 20 driver mutations are required for the cancer to become fully malignant [3]. Meanwhile heterogeneity of tumors has emerged as a general phenomenon for many cancer types and is defined as the observation that different tumor cells can take on different morphologic and phenotypic properties. Heterogeneity manifests in two ways, either within a single tumor (intra-tumor heterogeneity) or between different tumors (inter-tumor heterogeneity). A key to understanding heterogeneity is in unraveling the complex genomic diversity within a tumor, made possible by the advent of next generation sequencing (NGS) technologies. It is becoming more and more common for tumors from primary, metastatic and different spatial and temporal dimensions to be sequenced and studied, with efforts revealing the enormous genetic diversity and variability within and between tumors [4]. In prostate cancer (PCa), heterogeneity has been observed by pathologists at various levels: the primary tumor and its metastases, amongst separate tumors, and even within an individual tumor [5]. Genetic heterogeneity of cancers has recently been highlighted by studies that have used specific genetic markers for predicting cancer progression and aggressiveness [3], and even revealed the clonal origins of lethal metastatic PCa [6]. These studies have identified multiple mutations in commonly known oncogenic and tumor suppressor pathways, but dissecting out actionable mutations remains a challenge. A major confounding factor of the above studies is that the analyses were done on bulk tumors, which invariably lead to identification of genomic alterations of only the dominant clones. Thus, rare clones with genetic alterations that can potentially break out and give rise to aggressive forms of cancer might be missed. To overcome this, recent single-cell genomic strategies have been developed which have validated earlier observations of single-cell origin of metastatic disease [7]. An important study by Morrissey et al. exemplifies the potential translational utility that genomic and molecular insights into the nature of heterogeneity can provide. Their work centers on the transcriptomic analysis of disseminated tumor cells (DTCs) from primary prostate tumors. These cells can either lay dormant or seed to a distant site and progress to metastases and so researchers sought to identify a molecular signature associated with dormant DTCs [8]. They extracted and individually profiled 85 EpCAM+/CD45− cells from the bone marrow of PCa patients who either presented no evidence of disease (NED) or advanced diseased (ADV) and were able to cluster them 1 of 3 groups, NED, ADV_1, and ADV_2. Cluster analysis revealed heterogeneity within and between patients of NED and ADV groups, and two gene signatures were found from NED and ADV patients. Gene set enrichment analysis and Ingenuity Pathway Analysis performed on the 50 most up-regulated and 50 most down-regulated genes identified the p38 pathway as the most differentiated between NED and ADV_1 clusters, in that DTCs from patients with NED recurrence showed an up-regulation of genes belonging to the p38 pathway that are known to be associated with tumor dormancy [8]. Studies like these can provide a wealth of information in the discovery of future clinically relevant biomarkers (is this cancer predicted to lie dormant or metastasize?) and therapies (can we activate dormancy-inducing genes in aggressive disease?), and demonstrate the power that NGS and similar technologies have in recapitulating the complex molecular framework of PCas, and all cancers.
Taken together, ITH is a vast and intricate topic and comprises a variety of issues ranging from heterogeneity of a tumor and its surrounding microenvironment, heterogeneity of different cell types and their interactions with each other, and heterogeneity of genetic makeup of cells within the tumor. The focus of this review is to provide a picture of ITH in PCa in the context of ITH in other cancers.
Section snippets
Evolution of ITH
Historically, there have been two main models of ITH: the cancer stem cell model and the clonal evolution model (Fig.). The cancer stem cell model states that there is only a small set of cells that are tumorigenic, referred to as cancer stem cells. These cells often vary from the cell from which they originated, largely due to epigenetic factors or mutations caused by clonal evolution [9]. The clonal evolution model, first proposed in 1976 by Peter Nowell [10], suggests that cancer progression
ITH in solid tumors
Heterogeneity is ubiquitous as it is found in all cancer types, first observed as early as the 1800s [17] but genomic techniques have renewed present-day intrigue and interest in understanding the nature of heterogeneity. One of the first qualitative demonstrations of ITH was by karyotypic analysis of breast tumors by dividing individual tumors into several quadrants. Subclonal heterogeneity was observed with ≤9 distinct populations in a single quadrant of the same tumor [18]. Comparative
ITH in PCa
The ancient Egyptians were the first to document the occurrence of PCa [26]. Today, PCa exists as a leading cause of cancer-related “morbidity and mortality” in men. It is the second leading cause of death for men in the United States with an estimated 161,360 new cases and 26,730 deaths in the United States in 2017 alone [1]. Due to a lack of conclusive data from large screening trials and concerns about the large number of unnecessary biopsies that are being performed, current PCa diagnostic
Multifocality in PCa
PCa is frequently multifocal, as multifocal disease has been reported in 50% to 90% of all radical prostatectomy specimens and is associated with higher grade, stage and recurrence rate than unifocal PCa [34]; other estimations anticipate that nearly 80% of prostate specimens have more than one disease foci [35]. As an epithelial malignancy, prostatic adenocarcinoma has marked histological heterogeneity although the reason for its tendency to manifest in a multifocal manner remains unknown [36]
Origin of multifocality in PCa
There are many theories for the biological basis of PCa multifocality and heterogeneity. Morphological heterogeneity may be the result of tumor multifocality where, as the tumor volume increases over time, multifocal areas that may be of different grades move closer together and eventually fuse into a single large mass. As the multifocal tumors fuse there are fewer independent tumor foci, greater grade heterogeneity and increased tumor volume. A second hypothesis is that areas of poor
Tumor heterogeneity in metastasis
An important aspect of tumor heterogeneity is the relationship between primary and metastatic tumors, which can impact not only disease progression but could also influence the efficacy of current and future therapies. The systemic spread of cancer reflects the shedding of tumor cells into blood vessels and lymphatics to reach distant sites. There are 2 main models that have been put forth to explain this aspect of ITH. One predicts the acquisition of genetic abnormalities as a chance and
Conclusion
Intra-tumoral heterogeneity in PCa is an extremely important phenomenon not only for understanding tumor progression but also for determining the clinical course of the disease. The current state-of-the-art, though a step forward with several genomic tests being integrated into clinical practice, lacks in addressing the intricacies of ITH. We believe that progress depends on future efforts to thoroughly and systematically characterize ITH as it appears in the many subtypes PCa. This includes
Acknowledgments
The authors would like to thank the faculty of Department of Urology for helpful suggestions and discussions. Special thanks to Dr. Michael Droller for critical reading of the manuscript and providing helpful suggestions. Research in the lab is supported by funds from the Deane Prostate Health. Both K.K.Y. and S.S.Y. are supported by PCF Young Investigator Awards.
References (71)
- et al.
Clonal heterogeneity and tumor evolution: past, present, and the future
Cell
(2017) - et al.
Heterogeneity in primary and metastatic prostate cancer as defined by cell surface CD profile
Am J Pathol
(2004) - et al.
Evolution of the cancer stem cell model
Cell Stem Cell
(2014) - et al.
Single cell genome sequencing
Curr Opin Biotechnol
(2012) Intratumoral heterogeneity in breast carcinoma revealed by laser-microdissection and comparative genomic hybridization
Cancer Genet Cytogenet
(1999)Predictors of progression in Barrett’s esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression
Am J Gastroenterol
(2001)Heterogeneity of prostate cancer in radical prostatectomy specimens
Urology
(1994)Heterogeneity of PTEN and ERG expression in prostate cancer on core needle biopsies: implications for cancer risk stratification and biomarker sampling
Hum Pathol
(2015)Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer
Mod Pathol
(2014)Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study
Lancet Oncol
(2014)
Punctuated evolution of prostate cancer genomes
Cell
Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins
Eur Urol
Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies
J Urol
48 clinical genomics of advanced prostate cancer
Cell
Multifocal prostate cancer: biologic, prognostic, and therapeutic implications
Hum Pathol
Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing
Cell
Integration of copy number and transcriptomics provides risk stratification in prostate cancer: a discovery and validation cohort study
EBioMedicine
Tracking the origin of metastatic prostate cancer
Eur Urol
Small-molecule kinase inhibitors: an analysis of FDA-approved drugs
Drug Discov Today
Origins of metastatic traits
Cancer Cell
Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer
Cell Rep
Cancer of the Prostate—SEER Stat Fact Sheets [Internet]
The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries
Eur Spine J
Genetic progression and the waiting time to cancer
PLoS Comput Biol
Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer
Nat Med
The evolutionary history of lethal metastatic prostate cancer
Nature
Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways
Oncotarget
The clonal evolution of tumor cell populations
Science
Punctuated evolution caused by selection of rare beneficial mutations
Science
Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy
Clin Cancer Res
Tumor heterogeneity
Cancer Res
Paracrine signaling between tumor subclones of mouse SCLC: a critical role of ETS transcription factor Pea3 in facilitating metastasis
Genes Dev
The patterns and dynamics of genomic instability in metastatic pancreatic cancer
Nature
Tumor heterogeneity—a ‘contemporary concept’ founded on historical insights and predictions
Cancer Res
Karyotypic comparisons of multiple tumorous and macroscopically normal surrounding tissue samples from patients with breast cancer
Cancer Res
Cited by (59)
Prostate cancer: Molecular aspects, consequences, and opportunities of the multifocal nature
2024, Biochimica et Biophysica Acta - Reviews on CancerLiterature review: Imaging in prostate cancer
2023, Current Problems in CancerChemokines and cytokines: Axis and allies in prostate cancer pathogenesis
2022, Seminars in Cancer BiologyCitation Excerpt :Tumor heterogeneity has been established as a characteristic event for cancers, defined as monitoring different tumor cells showing distinct morphological and phenotypical properties [47]. Investigations at genomic, histopathological, and molecular levels have shown a high level of genetic and phenotypic diversity within the tumor [47]. This divergence of cells at the genetic level is the primary driver of tumor heterogeneity [48].
The evolution and ecology of benign tumors
2022, Biochimica et Biophysica Acta - Reviews on CancerExperimental challenges to modeling prostate cancer heterogeneity
2022, Cancer LettersCitation Excerpt :Intra-tumoral heterogeneity (ITH) is described as the presence of multiple cancer cell subpopulations, as well as non-tumoral cells including epithelial and non-epithelial lineages, within a tumor (e.g. cancer associated fibroblast CAFs) [41]. Multiple studies over the last years have demonstrated the high intra-tumor heterogeneity present in PCa [4,18,50–53]. The normal prostate gland has an acinar structure composed of three main epithelial cell types: basal cells, luminal cells, and rare neuroendocrine (NE) cells, as well as intermediate or progenitor cells.
From molecular mechanisms of prostate cancer to translational applications: based on multi-omics fusion analysis and intelligent medicine
2024, Health Information Science and Systems