Tumor heterogeneity described as having intertumoral heterogeneity or intratumoral heterogeneity.
Intertumoral heterogeneity can be defined as variations among tumors of different tissues and cell types, and variations between tumors of the same tissue type from different patients, and variations between different tumors within the same individual.
Intratumoral heterogeneity refers to variations of cancer as observed within a single tumor.
Tumor cell populations can differ by: cell surface markers, genetic or epigenetic changes, genetic stability, resistance or susceptibility to therapy, and varying growth rates.
Tumor heterogeneity describes the observation that different tumor cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential.
Tumor heterogeneity occurs both between tumours (inter-tumor heterogeneity) and within tumours (intra-tumour heterogeneity).
Intra-tumor heterogeneity is a consequence of the imperfection of DNA replication: whenever a cell divides, a few mutations are acquired leading to a diverse population of cancer cells.
Tumor heterogeneity is observed in leukemias/lymphomas, breast, prostate, colon, brain, esophagus, head and neck, bladder and gynecological carcinomas, liposarcoma, and multiple myeloma.
There are two models used to explain the heterogeneity of tumor cells: A cancer stem cell model and the clonal evolution model explain the heterogeneity of tumor cells.
Both models contribute to heterogeneity in varying amounts across different tumor types.
The cancer stem cell model asserts that within a population of tumor cells, there is only a small subset of cells that are able to form tumors.
These cells are termed cancer stem cells (CSCs), and are marked by the ability to both self-renew and differentiate into non-tumorigenic progeny.
The CSC model suggests that the heterogeneity observed between tumor cells is the result of differences in the stem cells from which they originated.
Stem cell variability is often caused by epigenetic changes, but can also result from clonal evolution of the CSC population where advantageous genetic mutations can accumulate in CSCs and their progeny.
Evidence of the cancer stem cell model has been demonstrated in multiple tumor types including leukemias, glioblastoma, breast cancer and prostate cancer, but it is still under debate.
The clonal evolution model proposes tumors arise from a single mutated cell, accumulating additional mutations as it progresses.
Such changes give rise to additional subpopulations, and each of these subpopulations has the ability to divide and mutate further.
Such heterogeneity may give rise to subclones that possess an evolutionary advantage over the others within the tumor environment, and these subclones may become dominant in the tumor over time.
The clonal evolution model allows understanding of tumor growth, treatment failure, and tumor aggression that occurs during the natural process of tumor formation.
Evolution of the initial tumor cell may occur by two methods:
Linear expansion and Branched expansion.
Sequential mutations accumulate in driver genes, tumor suppressor genes, and DNA repair enzymes, result in clonal expansion of tumor cells.
Branched expansion into multiple subclonal populations occurs through a splitting mechanism, and is more associated with tumor heterogeneity than linear expansion.
The acquisition of mutations is random as a result of increased genomic instability with each successive generation.
Multiple types of heterogeneity have been observed between tumor cells, stemming from both genetic and non-genetic variability.
Genetic heterogeneity is a common feature of tumor genomes, and can arise from multiple sources.
Some cancers are initiated when exogenous factors introduce mutations, such as ultraviolet radiation-skin cancers and tobacco=lung cancer.
More commonly a source is genomic instability, which often arises when key regulatory pathways are disrupted in the cells.
Some examples include impaired DNA repair mechanisms which can lead to increased replication errors, and defects in the mitosis machinery that allow for large-scale gain or loss of entire chromosomes.
Some genetic variability to be further increased by some cancer therapies.
Tumor cells can also show heterogeneity between their expression profiles, often caused by underlying epigenetic changes.
There is mechanochemical heterogeneity a hallmark of living cells.
The heterogeneous dynamic mechanochemical processes regulate interrelationships within the group of cell surfaces through adhesion.
Tumor development and spread is accompanied by change in dynamics of mechanochemical interaction process in the group cells, including cells within tumor.
Heterogeneity between tumor cells can be increased due to heterogeneity in the tumor microenvironment: Regional differences in the tumor impose different selective pressures on cells, leading to a wider spectrum of dominant subclones in different spatial regions of the tumor.
The microenvironment influence clonal dominance is also a reason for the heterogeneity between primary and metastatic tumor, as well as the inter-tumor heterogeneity observed between patients with the same tumor type.
Heterogeneic tumors exhibit different sensitivities to cytotoxic drugs among different clonal populations.
Drug administration in heterogeneic tumors seldom kills all tumor cells, allowing resistant tumor populations to replicate and grow.
This results in a repopulated tumor is heterogeneic and resistant to initial drug therapy used.
The repopulated tumor may also return in a more aggressive fashion.
The administration of cytotoxic drugs often results in initial tumor shrinkage with destruction of initial non-resistant subclonal populations within a heterogeneic tumor, leaving only resistant clones.
These resistant clones now contain a selective advantage and can replicate to repopulate the tumor, and may appear to be more aggressive.
This is attributed to the drug-resistant selective advantage of the tumor cells.
The level of heterogeneity can be used as a biomarker since more heterogeneous tumors may be more likely to contain treatment-resistant subclones.