Intratumoral heterogeneity and drug resistance in cancer

Abstract

Intratumoral heterogeneity is the main cause of tumor treatment failure, varying across disease sites (spatial heterogeneity) and polyclonal properties of tumors that evolve over time (temporal heterogeneity). As our understanding of intratumoral heterogeneity, the formation of which is mainly related to the genomic instability, epigenetic modifications, plastic gene expression, and different microenvironments, plays a substantial role in drug-resistant as far as tumor metastasis and recurrence. Understanding the role of intratumoral heterogeneity, it becomes clear that a single therapeutic agent or regimen may only be effective for subsets of cells with certain features, but not for others. This necessitates a shift from our current, unchanging treatment approach to one that is tailored against the killing patterns of cancer cells in different clones. In this review, we discuss recent evidence concerning global perturbations of intratumoral heterogeneity, associations of specific intratumoral heterogeneity in lung cancer, the underlying mechanisms of intratumoral heterogeneity potentially leading to formation, and how it drives drug resistance. Our findings highlight the most up-to-date progress in intratumoral heterogeneity and its role in mediating tumor drug resistance, which could support the development of future treatment strategies.

Keywords: Cancer; Drug resistance; Exosomes; Heterogeneity; Small extrachromosomal circular DNA.

Fig. 1

Intratumoral heterogeneity represented by cancer cells with different color in the context of tumor microenvironment resulting from different stromal cell compositions and biophysical properties such as differences in extracellular matrix composition (fibroblast), blood vessel (hypoxia and acidosis), and other factors

Fig. 2

Intratumoral heterogeneity can lead to drug resistance. A Anticancer drugs drive cancer cell evolution and new mutations, which mediates cell resistance. B Intratumoral heterogeneity pose a challenge to targeted therapies, subclonal lesions may be more effective of one targeted therapy

Fig. 3

EccDNA was randomly assigned to offspring cells to mediate intratumoral heterogeneity. A Mechanism of eccDNA formation (Ref Trends Genet. 2018 April; 34(4): 270–278). B EccDNA was randomly assigned to offspring cancer cells (Ref Int J Biol Sci. 2021; 17(4): 1010–1025) [174]. C The biological functions of eccDNAs [175]

Fig. 4

Exosomes released from the donor cells recognize and enter the recipient cells, thus ransferred exosomal resistant molecules triggers drug resistance