Tumor Biological Aspects of a Large-Scale Retrospective Study: The Role of Tumor Cell Heterogeneity, Inflammation and Aging in Survival

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Delay to Colectomy and Survival for Patients Diagnosed with Colon Cancer

In a recent large-scale retrospective study¹ an extensive institutional database of colon cancer patients was analyzed to explore the association between the wait-time for surgical colectomy and overall survival. The survival of patients who had a wait-time longer than 84 days was found to be poorer as compared to those who underwent surgery within 84 days. Furthermore, the authors found older age, male sex, higher Charlson comorbidity index, histological grade 4, and pathological grade III/IV to be the predictors of worse overall survival.

The study is a unique and indispensable work for several reasons. The number of involved patients and the follow-up time are high. Additionally, the individuals included in the study represent a histologically homogenous group of colon cancer patients. Also, the observed wait-time periods lasted for more than 84 weeks. The results of the study not just help to optimize health care resources in the surgical treatment of colon cancer, but draw attention to many complex, interrelated tumor biology phenomena that need to be considered during the daily routine.

Advanced pathological stage and high histological grade of colon cancer were found to be predictors of worse overall survival. However, survival within a particular stage can be highly variable depending on -among others- the grade of the tumor.² Tumor grade applied for colon cancer has long been based on the degree of differentiation, which is difficult to judge objectively. Conventional histological examination of biopsy samples or even surgical specimens is not always suitable for correct determination of histological grade. Human cancers are characterized by high heterogeneity in gene expression, varieties of differentiation phenotypes and tumor-host interactions. Nowadays, the tumorigenesis theory which states that specific phenotypic subpopulations of cancer stem cells (CSCs) are responsible for tumor development, production of heterogeneous differentiated tumor mass, metastasis, and resistance to therapies has become widely accepted. Since the stemness-related gene expression patterns in colonospheres are different,³ the exact determination of intratumoral cell heterogeneity could be a useful and novel criterion for subclassification.⁴ By using a newly developed method (i.e., hydrogel microstructure array – HMA) several levels of cancer cell heterogeneity, including morphological and phenotypic variability, differences in both proliferation capacity and drug response can be defined.⁵ Moreover, the system facilitates the examination of drug-induced alteration in expression of stemness markers. The HMA technology may be applicable in multiplex ex vivo analysis of different patient-derived tumor specimens, detection and characterization of potentially dangerous cell phenotypes, and for distinctive evaluation of drug sensitivity of CSCs and other types of cancer cells.

The study¹ could be the basis for future experiments where histological grade subclassified according to different levels of tumor cell heterogeneity may improve prognostication and may impact therapeutic decisions.

According to the outcomes of the study¹ a wait-time longer than 84 days resulted in a poorer survival as compared to shorter preoperative waiting time-frames. Older age was determined as a risk factor for the longer wait-time. Since cancer is associated with aging, immunological features in the aged should be considered when planning curative surgery. Recent findings provide evidence that chronic inflammation plays a role in colonic carcinogenesis in older adults.⁶ In an experimental model of colon cancer impaired antitumor immunity resulted in accelerated tumor growth in aged mice compared with that in young animals.⁷ The explanation of this phenomenon can be the impaired priming of tumor-specific cytotoxic T-lymphocytes (CTLs) due to the elevated serum levels of proinflammatory cytokines such as IL-6 and TNF-α. In vivo neutralization of IL-6 showed a tendency to restore the in vitro induction of tumor-specific CTLs. Alternatively, after the suppression of inflammation in tumor-bearing hosts the in vivo priming of tumor-specific CTLs was improved in aged mice.⁷

Additionally, the influence of aging on T-cell compartment is defined by the reduction of thymic production, and CD4+ T-cell lymphopenia. Further, intrinsic defects affecting T-cell responsiveness such as altered cell membrane fluidity, changes of the expression of co-stimulatory molecules and cytokine receptors, molecular and transcriptional changes, and a shift from naïve towards effector/memory T-cells have also been reported.⁸ However, in mice an inverse correlation was detected between the CD4+ T-lymphocyte numbers in secondary lymphoid organs and colonic lamina propria. Interestingly, the concomitant accumulation of CD4+ T-cells in gut-associated lymphoid tissue (GALT) and their depletion in secondary lymphoid organs during aging was observed both in male and female animals. The inverse correlation of CD4+ T-cell numbers and the absence of obvious proliferation in GALT suggest that the aging-associated CD4+ T-cell decline in secondary lymphoid organs reflect a redistribution of CD4+ T-lymphocytes rather than a generalized CD4+ T-cell decay.⁸

The age-related presence of chronic inflammation, the differences in T-cell priming, and the tissue-specific redistribution of T-cells may influence the effectivity of antitumor immunosurveillance, therefore could contribute to the differential prognosis of patients with colon cancer. In addition, immunophenotyping of tumor-infiltrating and peritumoral immune cells may open a new avenue for the management of patients with colon cancer.

Higher Charlson comorbidity index was also determined as a predictor of worse overall survival. The examined index, in part, consists of the presence of diabetes mellitus, liver diseases (including fatty liver disease and non-alcoholic steatohepatitis), and different types of atherosclerosis. These disorders are all part of metabolic syndrome (MetS), a chronic inflammatory disorder, in which the role of proinflammatory cytokines, reactive oxygen species (ROS) and free fatty acid intermediaries have been suggested as key factors in modulating specific intracellular signaling pathways that appear to regulate insulin sensitivity.⁹ MetS is associated with the development of several types of tumors including colon cancer.⁹ Tissue injury caused by various spectrum of agents may elicit a chronic immune response leading to cell proliferation, enhanced regeneration, and altered autophagy. When the immune response fails to resolve injury, the inflammatory milieu rich in cytokines, growth factors, and ROS participates in accumulation of genetic errors and a sustained inappropriate proliferation, hence the subsequent development of colon cancer. The complexity of the insulin-like growth factor (IGF)/ IGF-receptor 1 (IGF1R) pathway and the autophagy machinery may partly account for this failure.¹⁰ Recent data suggest that inhibition of IGF/IGF1R system along with manipulation of the autophagy process could play an important role in suppressing MetS-related inflammatory and cancerous disorders of the colon.¹⁰ On the other hand, IGF1R inhibition may lead to a decrease in mTORC2 (mammalian target of rapamycin complex 2) function, which, in turn, reduces the activity of protein kinase C α and β, and so, affects the autophagosome formation by modulating the cytoskeleton and the rate of endocytosis.¹⁰ According to these results caution is required, since the pharmacologic modulation of the IGF1R – autophagy machinery may initiate further, sometimes undesirable immunobiological outcomes.

Considering the above-mentioned tumor biological aspects, the study¹ may be the starting point for future large-scale retrospective studies designed to examine the association between the preoperative wait-time and overall survival in the case of such colon cancers that developed on other pathological pathways (e.g.: colitis-associated cancers, serrated adenoma pathway, de novo pathway).

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.