Tumor Heterogeneity
Tumors are usually composed of billions of malignant cells that may differ genetically, thus generating a genetically diversified tissue mass. During the process wherein a single progenitor cell divides into billions of tumor cells, genetic alterations accumulate sequentially. In this way, they provide footprints for tracing the evolution and development history of a tumor and helping reconstruct the phylogenetic trees. This is important in understanding how tumors initiate, expand, disseminate, and give rise to metastases at distant sites.
Fig.1 Timeline of the development of perceptions of tumor heterogeneity. (Zhu, 2021)
Types of Tumor Heterogeneity
There are several types of genetic heterogeneity in cancer biology.
- Interpatient tumor heterogeneity is the most well-known type of tumor heterogeneity, wherein no two patients with the same subtype of tumor behave the same clinically, with or without treatment. This may be related to host factors, such as tumor microenvironment and germline variants influencing treatment response, together with the unique somatic mutations that may occur within the tumor of each individual patient.
- Intratumor heterogeneity. It describes the existence of distinct cellular populations with specific genetic, epigenetic, and phenotypic features within tumors and has long been recognized.
- Intermetastatic heterogeneity. Metastatic lesions at different secondary sites can arise from different cell populations within a primary tumor, resulting in heterogeneity among metastases.
- Intrametastatic heterogeneity. Metastatic lesions can acquire new mutations and evolve independently with each cell division, heterogeneity within a metastasis can also exist, known as intrametastatic heterogeneity. This is associated with multiple mechanisms of acquired drug resistance in the same patient with metastatic disease.
Fig.2 Different types of tumor heterogeneity. (Mariam, 2015)
Tumor Heterogeneity and Cancer Progression
Scientists found that the presence of a subclonal driver was an independent risk factor for disease progression. Furthermore, patients treated with cytotoxic chemotherapy were more likely to undergo clonal evolution, as the heterogeneity evolved during treatment. Studies like this indicate the potential relevance of tumor heterogeneity in predicting adverse outcomes and the evolution of tumor subclonal composition during treatment. Therefore, it may not always be the case that the dominant clone dictates tumor growth and malignant potential.
Heterogeneity in the tumor microenvironment may also influence the evolution and progression of tumors. For example, interactions between tumor and stromal cells, changes in the level of hypoxia or acidity, increased or decreased inflammatory cell infiltrate, and remodeling of the extracellular matrix, all may act as selection pressures and lead to increased phenotypic heterogeneity, potentially influencing treatment response and, therefore, tumor evolution.
Fig.3 Clonal evolution and development of tumor heterogeneity. (EI-Sayes, 2021)
Therapeutic Failure and Resistance
Heterogeneous tumors are composed of multiple subclones. Under selection pressures, such as chemotherapy, subclones with either intrinsic or acquired resistance can be selected, allowing these subclones to dominate a tumor mass and potentially drive disease progression. The selection of resistant subclonal populations as a result of therapy leading to treatment resistance has been shown in several tumor types, including lung, colorectal, gastrointestinal, and brain tumors, and chronic myeloid leukemia, among others.
Mechanisms of Resistance
The mechanisms by which a tumor develops resistance may involve multiple somatic events affecting distinct signal transduction pathways, resulting in multiple distinct drug resistance events within the same patient’s tumor burden, which poses considerable challenges for designing and selecting effective drug combinations. However, there is evidence for phenotypic convergence within and across tumor types, suggesting that genetic events driving resistance and disease progression may focus on either one or several signaling pathways that may be therapeutically targetable.
Fig.4 Intratumor heterogeneity and clonal evolution. (Mariam, 2015)
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References
- Zhu, L.; et al. A narrative review of tumor heterogeneity and challenges to tumor drug therapy. Annals of Translational Medicine. 2021, 9(16): 1351.
- Mariam, J.H.; et al. Translational implications of tumor heterogeneity. Clinical Cancer Research. 2015, 21(6): 1258-1266.
- EI-Sayes, N.; et al. Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy. Cancers. 2021, 13(4): 806.
