Turning the headlights on novel cancer biomarkers: Inspection of mechanics underlying intratumor heterogeneity

Abstract

Although the existence of intratumoral heterogeneity (ITH) in the expression of common biomarkers has been described by pathologists since the late 1890s, we have only recently begun to fathom the staggering extent and near ubiquity of this phenomenon. From the tumor’s perspective, ITH provides a stabilizing diversity that allows for the evolution of aggressive cancer phenotypes. As the weight of the evidence correlating ITH to poor prognosis burgeons, it has become increasingly important to determine the mechanisms by which a tumor acquires ITH, find clinically-adaptable means to quantify ITH and design strategies to deal with the numerous profound clinical ramifications that ITH forces upon us. Elucidation of the drivers of ITH could enable development of novel biomarkers whose interrogation might permit quantitative evaluation of the ITH inherent in a tumor in order to predict the poor prognosis risk associated with that tumor. This review proposes centrosome amplification (CA), aided and abetted by centrosome clustering mechanisms, as a critical driver of chromosomal instability (CIN) that makes a key contribution to ITH generation. Herein we also evaluate how a tumor’s inherent mitotic propensity, which reflects the cell cycling kinetics within the tumor’s proliferative cells, functions as the indispensable engine underpinning CIN, and determines the rate of CIN. We thus expound how the forces of centrosome amplification and mitotic propensity collaborate to sculpt the genetic landscape of a tumor and spawn extensive subclonal diversity. As such, centrosome amplification and mitotic propensity profiles could serve as clinically facile and powerful prognostic biomarkers that would enable more accurate risk segmentation of patients and design of individualized therapies.

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

“…It has been proposed that alterations resulting in genome instability happen early during tumor formation, allowing the accumulation of errors during DNA replication, repair, and chromosome segregation, thereby increasing the likelihood that a cell will acquire multiple genetic changes necessary for tumor progression (4). CIN is possibly the major contributor to intratumoral heterogeneitythat is, the presence of genetically distinct populations of cells within a single tumor that impacts treatment strategy, drug resistance, and tumor evolution (5)(6)(7)(8). For these reasons, defining genes and pathways that drive CIN and understanding the mechanisms that underlie genome stability will contribute not only to an understanding of tumor etiology and progression but will also be relevant for guiding therapeutic strategies.…”

Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas

“…CA, a key driver of CIN and an early driver of intratumoral heterogeneity [32], is associated with tumorigenesis and tumor progression in multiple cancers, including that of the head and neck. Previous studies in surgically resected HNSCCs have shown an association between higher CA and local recurrence, with CA being a better predictor of recurrence than other commonly used parameters such as T stage [33,34]; furthermore, higher CA has been linked with poor overall survival in HNSCCs [35].…”

A Practical Approach to Tumor Heterogeneity in Clinical Research and Diagnostics

“…Recently for CIN the use of γ-tubulin antibodies has been proposed to detect in tissues centrosome amplification, which could be a possible major cause of CIN in tumors [92]. Centrosome amplification has already been detected in many cancers, such as breast, prostate, pancreatic, colon, and ovarian cancers [93,94].…”