Biomarker: S-phase fraction (SPF)

Biomarker subtype: DNA

Clinical application: prognosis(unfavorable)

Histology type: endometrial carcinoma

Country: Sweden

Region: Uppsala

Followed up time : 78 months.

Sample type : tissue

Clinical method: flow cytometry

Description: Ki-67 and, to a lesser extent, PCNA, give approximate estimates of the growth fraction, whereas SPF only reflects the proportion of cells in S-phase. However, SPF is by far the strongest predictor of survival.

Detailed Description: Cellular growth fraction is the percentage of proliferative cells, in cell cycle, in a tumor, and that therefore contribute to its growing.[http://www.biocancer.com/journal/768/21-compartimentos-celulares]Although all cells go through the same sequence of phases, there are differences in the number of proliferative cells that constitute a tissue or a tumor. In a given neoplasia, the number of cells in cycle or in growth is only a minority; most of them are in G0, differentiated to the point of losing their replication capacity, or dead.To understand tumor growth it is necessary to know the concept of tumor doubling time, referring to the time it takes for the number of cells to double.2 The tumor doubling time is defined by growth fraction and cell loss rate. Most of tumors have a low growth fraction along with a high rate of cell loss, further limiting tumor growth. In other words, tumor doubling time increases. Part of the cell loss is due to the genetic instability of daughter cells, which can lead to apoptosis or to ischemic necrosis phenomena.2Tumor growth fraction is closely related to tumor volume, being both inversely proportional. This is because tumor cell populations follow a Gompertzian growth model.[García-Conde J. Oncología clínica básica [Internet]. Arán; 2000. Available from: https://books.google.es/books?id=co3E3qO8_zoC] All cell populations seem to have a larger number of cells in division when the population size is small, and they start to decrease while the size grows. Biological growth that follows this pattern is known as Gompertzian growth. This growth model is also applicable in oncology, as in most neoplasms tumor growth fraction decrases as the volume of the tumor progresses. In early stages growth is exponential, with a high growth rate and a very short doubling time. The growth fraction reaches its maximum value when tumor size is about 37% of its lethal volume, and as the tumor grows, doubling time increases and growth fraction decreases.Although the mechanisms that lead to tumor growth retardation are not entirely known, among the involved factors are hypoxia and reduced availability of nutrients and growth factors, as increased tumor volume implies a greater distance from the capillaries, toxic metabolites accumulation, and intercellular inhibitory communication.2Another important factor of tumor kinetics because of its role in the effectiveness of treatments is that proliferating cells, which are the most vulnerable, are not necessarily the cells to be removed in order to eradicate the tumor. Cancer stem cells, responsible for the persistence and the growth of the tumor are mainly in G0, with an unlimited capacity for self-replication.Recent studies prove that hypoxia promotes stem cell maintenance and blocks differentiation, thus its critical role in defining cellular sensitivity to radiation may link additional processes of stem cell maintenance and therapeutic resistance.[ Rich JN. Cancer Stem Cells in Radiation Resistance. Cancer Res [Internet]. 2007 Oct 1;67 (19 ):8980–4. Available from: http://cancerres.aacrjournals.org/content/67/19/8980.abstract] Cancer stem cells also play an important role in tumor angiogenesis, and therefore in tumor growth, worsening prognosis.Since hypoxia is a key element of radioresistance, new cancer treatments should be focused on treating tumors in the earliest possible stage, where it is minimal, thus favoring a better therapeutic response.[http://www.radiologyandphysicalmedicine.es/tumor-growth-parameters-growth-fraction/]