Clinical implications of intratumor heterogeneity: challenges and opportunities

Abstract

In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and biological ramifications this phenomenon poses. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Functionally, heterogeneity provides tumors with significant adaptability. This ranges from mutual beneficial cooperation between cells, which nurture features such as growth and metastasis, to the narrow escape and survival of clonal cell populations that have adapted to thrive under specific conditions such as hypoxia or chemotherapy. These dynamic intercellular interplays are guided by a Darwinian selection landscape between clonal tumor cell populations and the tumor microenvironment. Understanding the involved drivers and functional consequences of such tumor heterogeneity is challenging but also promises to provide novel insight needed to confront the problem of therapeutic resistance in tumors.

Sequential 3D OrbiSIMS and LESA-MS/MS-based metabolomics for prediction of brain tumor relapse from sample-limited primary tissue archives

“…interpreted as a more homogeneous distribution across the tumor area in both groups (ANOVA: p = 0.0039). Increased intra-tumor heterogeneity has previously been identified as an important indicator for therapy resistance and poor overall survival (46)(47)(48). However, for L-phenylalanine, we did not observe a difference in heterogeneity (dynamic range) between both groups (Student's t-test: p = 0.9443; Fig.…”

Dual Targeting of Endothelial and Cancer Cells Potentiates In Vitro Nanobody-Targeted Photodynamic Therapy

“…Intratumoral heterogeneity is one of the leading causes of therapeutic resistance and treatment failure, and one of the main reasons for poor overall survival in cancer patients. Importantly, it has been shown that targets against which therapeutics are available are not expressed in a homogeneous manner in tumor tissues [ 21 , 22 , 38 ]. Therefore, combination approaches that target cancer cells and tumor vasculature can potentiate the therapeutic response [ 40 ].…”

“…Following up on the promising results we obtained in both in vitro and in vivo studies, we explored the possibility of combined targeting of endothelial and cancer cells in vitro, in order to improve the efficacy of targeted PDT. We hypothesized that dual targeting of receptors on endothelial and cancer cells is likely beneficial in tumors with high heterogeneity of target expression and/or intermediate/low target expression levels [ 21 , 22 ]. In line with this, our previous study showed that dual targeting of two cancer cell targets, namely HER2 and CAIX, improved tumor imaging in an orthotopic model of breast cancer [ 23 ].…”

New paradigms and perspectives in cancer research in Spain

“…De hecho, esto podría generar en el futuro una novedosa terapia personalizada para la metástasis en la que se proporcionarían medicamentos específicos para desafiar la viabilidad de las células cancerosas que atienden a los órganos moleculares clave específicos de cada órgano. (Figura 3 y 4) d) Buscando factores de embudo o centrales de señalización , el Dr. Ramón y Cajal (12,13) presentó los datos clínicos de la expresión de factores de señalización en tumores humanos. La expresión fue bastante heterogénea en la mayoría de ellos (pAKT, pmtor, pMAPK, pS6) pero 4EB-P1 y especialmente peIF4E que se sobreexpresaron en las células tumorales.…”