Malignancy-associated changes

Schwab (ed.), Encyclopedia of Cancer, Springer-Verlag Berlin Heidelberg 2015


Malignancy-associated changes (MACs) are subtle changes in the nuclear morphology and chromatin structure of seemingly normal cells located proximal or even distal to neoplastic or preneoplastic lesions.


MACs were first described nearly 100 years ago in the leukocytes of patients harboring malignant disease, though the term “MAC” was not applied until the 1950s when these features were observed in normal buccal mucosa. The hallmarks of MAC are a variety of changes in nuclear texture, including increases in the ratio of nucleus to cytoplasm, disappearance of nucleoli, emergence of specific arrangements for chromatin bands and nuclear proteins, and the presence of multinucleated cells.

Although MACs were observed in the nuclei of tumor-associated peripheral blood, sputum, bone marrow, uterus, pancreas, liver, and skin cells, the subjective approaches for determining these features limited their use in a clinical setting. The development of image cytometry techniques in the 1970s allowed objective measurement of this phenomenon, raising the potential for clinical application. Densitometric analysis of Feulgen-stained nuclei by a camera with a charge-coupled device was used to objectively assess MACs. This stain binds to DNA, allowing characterization of chromosomal features, while the camera’s high resolution facilitates hundreds of precise independent measurements of nuclear size, shape, and volume. The spatial organization of genomic material within the nucleus is another metric for assessing MAC effect. This includes the assessment of whether DNA is dispersed to the edges of the nucleus or clumped at the center, the degree of contrast between condensed and non-condensed chromatin, and whether chromosomes are found in large irregular clumps or small uniform clumps. Ultimately, the development of high-resolution imaging approaches has facilitated analysis of more than 60 different cell features – many of which cannot be detected by the human eye – to identify MACs.


Two general mechanisms have been used to explain how MACs arise. The first is that MACs develop in normal tissue neighboring tumors due to exposure to the same carcinogens that induced the tumor. This “field effect” explanation proposes that MACs arise independently from neighboring tumor tissue. The second proposed mechanism is that MACs arise in normal cells due to soluble factors that are released from tumor tissue. That is, the tumor induces changes in surrounding normal tissue.

One avenue of support for the second explanation is that the degree of MAC in normal cells escalates with increasing lesion severity (e.g., MACs in normal uterine cervical cells have been shown to increase with cancer progression). Further support for the idea that MACs arise in a tumor-dependent fashion is the fact that MACs in normal cells diminish after tumor has been removed. Additional support for this tumor-dependent model can be found in the fact that MAC severity in normal cells can decrease depending on the distance from a given lesion and that in vitro experiments involving the maintenance of normal cells and tumor cells in the same culture flask show that the number of MACs in the normal cells increases when the concentration of cocultured tumor cells increases.

Dysregulation of growth factors is well characterized in a variety of tumor types, and autocrine signaling is understood to drive unchecked cell cycle progression. It is possible that neighboring normal cells are susceptible to the effects of this mode of activation; normal cells expressing growth factor receptors on their outer membrane could be susceptible to aberrant activation through paracrine signaling. Redistribution of chromatin is also a hallmark of MAC.

Chromatin remodeling in cancers has previously been described and is known to result in oncogenic activation. In normal cells exhibiting MACs, these changes may alter transcriptional activity in various parts of the genome, which may in turn lead to activation of genes that drive other observable MACs.

Clinical aspects

High-resolution genomic technologies have been used to uncover specific factors associated with MACs. For example, gene expression microarray studies of airway epithelial cells from smokers with and without lung cancer revealed specific changes associated with the presence of disease. Upregulated genes were involved with inflammation and cell cycle progression processes, including multiple factors associated with the oncogenic RAS (Ras Genes) signaling pathway, suggesting that the presence of cancer mediates the behavior of normal airway tissue.

MACs could have utility as surrogate biomarkers in at-risk populations (e.g., smokers with risk of tobacco-related cancer). Where individuals are asymptomatic and have no detectable tumor mass, the presence of MACs may be used to identify patients requiring greater clinical vigilance, including regular screening for disease. For example, MACs have been shown to improve sensitivity for detecting early lung cancers when used in conjunction with conventional approaches to sputum cytology. (The ability to couple MACs with noninvasive diagnostic approaches also makes it an attractive tool for clinical application.) Discovery of additional MAC-associated factors will increase the likelihood that these changes will be adopted as screening tools in the clinic.


Autocrine signaling

Occurs where a chemical messenger released by a cell stimulates receptors on that same cell, inducing changes in cellular behavior.


Complex in the nucleus comprised of DNA and proteins (mainly histones) that condenses into chromosomes during cell division.

Paracrine signaling

Occurs where a chemical messenger released by a cell stimulates receptors on that same cell, inducing changes in cellular behavior.


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