Hallmarks of cancer

Cancer (malignant neoplasms) is a broad group of approximately 200 diseases. Cancer is signified by dysregulated and autonomous cell growth, with attainable spread and growth in distant organs. A tumor lacking these features is denoted benign.

Many factors are known to increase the risk of cancer, including tobacco use, certain infections, radiation, obesity and environmental pollutants. The underlying cause for transformation of a normal cell to a cancer cell is mutations in genes important for growth regulatory functions, differentiation, cell survival and apoptosis. The malignant transformation process is a clonal evolution driven by a sequential accumulation of mutations, and is initiated by a first mutation in a single progenitor cell. The acquired mutations confer new biological properties characteristic of malignant cells, described by Hanahan [1] as six acquired "hallmarks of cancer". These hallmarks include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Since the first publication in 2000 this roster has been complemented with an additional two "emerging hallmarks"[2]. Deregulating cellular energetics, which enables a reprogrammed metabolism for support of neoplastic proliferation, and avoiding immune destruction, which allows cancer cells to evade immunological destruction. As stated above, the acquisition of hallmarks of malignancy depends in large on a succession of DNA alterations. The rate of spontaneous DNA mutations are usually very low, and defects in genome maintenance and repair are instrumental for tumor progression, and genomic instability and mutation has therefore been added to the roster as an enabling characteristic along with tumor-promoting inflammation. Tumor-promoting inflammation describes the paradoxical effect of tumor-associated inflammatory cells in enhancing tumorigenesis and progression.

The accumulating genetic changes ultimately leading to cancer cause not only functional disruptions but also morphological changes. The well studied morphological evolution of colorectal cancer for example, where precancerous adenomas evolve into invasive and eventually metastasizing cancer, is well in accordance with the hypothesis of a sequential accumulation of mutations. The first manifestations of neoplasia in colorectal epithelium (adenoma) eventually evolve into cancer when and if one of the cells in the adenoma acquires necessary mutations to drive the processes of invasion and metastasis. Consequently, morphological assessment is today still the golden standard to determine a cancer diagnosis, including subtype, stage of tumor growth and grade of malignancy. Malignant tumors display features such as cellular atypia, altered differentiation, increased proliferation (mitoses), necrosis, inflammatory response and overall disordered tissue architecture (wrong cells in wrong locations).

The wide range of possible progenitor cells in combination with a plethora of possible mutation spectra renders cancer a complex and highly heterogeneous disease. Epithelial tumors are the most common forms of cancer and include adenocarcinoma, representing tumors originating from glandular epithelia, and squamous cell carcinoma, representing tumors arising from cells in squamous epithelia. In addition, squamous cell carcinoma can be derived from glandular cells that have undergone squamous metaplasia prior to malignant transformation, e.g. cervical and lung squamous cell carcinoma. Microscopic evaluation is needed to distinguish if a cancer is in an early, not yet invasive form (in situ cancer) or invasive. For invasive cancer it is furthermore important to determine the stage of tumor growth, i.e. the extension of tumor growth in context to surrounding normal tissues and metastatic spread to lymph nodes and distant organs. The accepted classification for determining stage of tumors is based on the TNM system, which defines criteria for each tumor type regarding extension of primary tumor (T), metastases in lymph nodes (N) and metastases at distant sites (M).

Tissue morphology is also the basis for subclassification of cancer into defined different categories each with different prognosis and response to treatment. One important general aspect of such classification involves the degree of differentiation that a tumor displays, since the level of differentiation and the level of malignancy in general show a negative correlation. A highly differentiated cancer is more similar to the corresponding normal phenotype and has in general a relative low malignancy grade whereas in poorly differentiated cancers, tumor cells are highly proliferative and lack features that are found in normal counterpart cells and show a higher grade of malignancy. For several forms of cancer defined protocols for determining grade of malignancy have been established, for example the Elston-Ellis and Gleason scoring systems for breast and prostate cancer respectively. Malignancy grading systems for various cancer types are generally based on the central features of cancer, i.e. differentiation, proliferation and cellular atypia.

[1] Hanahan, D., Weinberg, R. A., Cell 2000, 100, 57-70.

[2] Hanahan, D., Weinberg, R. A., Cell 2011, 144, 646-674. Elsevier user licence.