Demystifying the Differences Between Tumor-Initiating Cells and Cancer Stem Cells in Colon Cancer

Purpose of Review

Tumor-initiating cells and cancer stem cells refer to a subpopulation of self-renewing cells involved in tumor initiation and tumor maintenance, respectively. With this review, we aimed to define the functional and molecular differences between both cell types in the context of colon cancer.

Recent Findings

Recent evidence suggests that the two major stem cell populations in the normal intestinal crypt have tumor-initiating capacity and could be the cell-of-origin in colon cancer. Activation of the Wnt/β-catenin pathway (an early event in mouse intestinal carcinogenesis) in the crypt base columnar stem cells and reserve stem cells leads to adenoma formation, supporting a role in tumor initiation. On the other hand, colon cancer stem cells express several membrane markers facilitating their isolation by FACS and are associated with treatment resistance and higher metastatic potential.

Summary

Tumor-initiating cells and cancer stem cells express distinct markers, display discrete biological functions, and can be studied using different molecular and cellular approaches. While cancer stem cells may be derived from tumor-initiating cells, these terms are not necessarily interchangeable and more likely reflect a specific cell state.

     

Suppression of Acquired Docetaxel Resistance in Prostate Cancer through Depletion of Notch- and Hedgehog-Dependent Tumor-Initiating Cells

Acquired resistance to Docetaxel precedes fatality in hormone-refractory prostate cancer (HRPC). However, strategies that target Docetaxel resistant cells remain elusive. Using in?vitro and in?vivo models, we identified a subpopulation of cells that survive Docetaxel exposure. This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis. Notably, targeting Notch and Hedgehog signaling depleted this population through inhibition of the survival molecules AKT and Bcl-2, suggesting a therapeutic strategy for abrogating Docetaxel resistance in HRPC. Finally, these cells exhibited potent tumor-initiating capacity, establishing a link between chemotherapy resistance and tumor progression.     

Venetoclax in AML: Where We Are and Where We Are Headed

The developmental path for venetoclax in acute myeloid leukemia (AML) has been rapid and stands in stark contrast to the incremental progress that has characterized the field in previous decades. For perspective, on December 31, 2013, the first AML patient was enrolled into a study using venetoclax; 59 months later, on November 21, 2018, venetoclax received accelerated approval by the FDA for use in AML. In June 2020, Dr. DiNardo presented the results of the required confirmatory study at the European Hematology Association meeting, showing that venetoclax with azacitidine resulted in a superior response rate and overall survival compared to azacitidine alone for older, newly diagnosed AML patients. This swift progress has provided a welcome and potent new therapy for patients with AML; with it come questions about how its role can be expanded, and how its use can be optimized.     

Overexpression of LACTB,a Mitochondrial Protein That Inhibits Proliferation and Invasion in Glioma Cells

LACTB, a mitochondrial protein, was ubiquitously expressed in different mammalian tissues, such as liver, heart, and skeletal muscle. It has been shown that LACTB is downexpressed in breast cancers, and it suppresses the proliferation and promotes the apoptosis of breast cancers. However, its role in the progression and prognosis of glioma remains unknown. In this study, we analyzed the clinicopathological features and outcomes of LACTB expression in 98 glioma patients and investigated the effects of LACTB overexpression on the proliferation, invasion, and angiogenesis of glioma cells in vitro. We observed a significant decrease in LACTB expression in glioma, and downexpression of LACTB is correlated with a poor prognosis of glioma patients. Moreover, Cox regression analysis reveals that the LACTB is an independent prognostic indicator for glioma patients. Overexpression of LACTB could suppress the proliferation, invasion, and angiogenesis of glioma cells. In addition, overexpression of LACTB could inhibit the expression of PCNA, MMP2, MMP9, and VEGF. Taken together, these data indicate that LACTB may serve as a promising therapeutic target for gliomas.     

Treatment of Advanced BRAF-Mutated Colorectal Cancer: Where We Are and Where We Are Going

In recent years, studies on the molecular typing of colorectal cancer have matured, and the V-raf murine sarcoma viral oncogene homolog B (BRAF) of the mitogen-activated protein kinase pathway has been shown to be an important effector molecule of this pathway and regulates the occurrence and development of colorectal cancer. Clinical observations indicate that colorectal cancer patients harboring the BRAF V600E mutation have a worse prognosis than BRAF wild type patients. Several resistance mechanisms have been identified that have led to the development of different treatment strategies, which have shown encouraging activity in early clinical trials. Therefore, a reasonable combination of targeted therapies is expected to further enhance the efficacy of selective BRAF inhibitors. Moreover, some CRC patients with high microsatellite instability or a mismatch repair deficiency seem to be susceptible to checkpoint inhibitors with objective and sustained clinical responses, providing new opportunities for patients with advanced disease. This article primarily explores 3 aspects of the treatment strategies for advanced BRAF-mutated colorectal cancer; chemotherapy, targeted therapy, and immunotherapy.     

Harnessing a Different Dependency: How to Identify and Target Androgen Receptor-Positive Versus Quadruple-Negative Breast Cancer

The androgen receptor (AR) is a promising therapeutic target for a subset of triple-negative breast cancers (TNBCs) in which AR is expressed. However, the mechanistic action of AR and the degree to which primary and metastatic tumors depend on AR, both before and after conventional treatment, remain to be defined. We discuss preclinical and clinical data for AR+ TNBC, the difficulties in monitoring AR protein levels, new methods for determining AR status, the influence of AR on “stemness” in the context of TNBC, the role of combined inhibition of sex steroid production and AR, and the role of AR in regulation of the immune system. Although the exact role of AR in subsets of TNBC is still being characterized, new therapies that target AR and the production of androgens may provide additional options for patients with TNBC for whom chemotherapy is currently the sole treatment option.     

Single Life Time Cytological Screening in High Risk Women as an Economical and Feasible Approach to Control Cervical Cancer in Developing Countries Like India

In view of funding crunches and inadequate manpower in cytology in developing countries like India, singlelifetime screening for cervical cancer has been suggested. In this study, an attempt was made to identify highrisk groups of women for this screening to make it more effective for early detection. Cytological data werederived from the ongoing routine cervical cytology screening program for women attending Gynaecology OutPatient Department of Queen Mary’s Hospital of K.G.Medical University, Lucknow, India during a span of 35years (April 1971 - December 2005). Cervical smears in a total of 38,256 women were cytologically evaluated.The frequencies of squamous intraepithelial lesions of cervix (SIL) and carcinoma cervix were found to be 7.0%and 0.6%, respectively, in the series. Predisposing factors related to cervical carcinogenesis were analyzed indetail to establish the most vulnerable groups of women for single life time screening. The incidence of SIL andcarcinoma cervix was found to be maximal in women above the age of 40 years irrespective of parity and inmultiparous women (with three or more children) irrespective of age. The incidence of cervical cytopathologieswas significantly higher in symptomatic women, the frequency of SIL being alarmingly higher in womencomplaining of contact bleeding and that of carcinoma cervix in older women with postmenopausal bleeding.It is consequently felt that single life time screening must include the three groups of women delineated above.Such selective screening appears to be the most economical, cost effective and feasible approach to affordablycontrol the menace of cervical cancer in developing countries like India.