Cancer stem cells related marker CD44 and Notch activation in metastatic colon cancer patients.

474 Background: Although an oxaliplatin-based adjuvant treatment is a widely accepted option for radically resected stage III colorectal cancer patients, it is not uncommon to observe an heterogeneous clinical outcome independently from stage. Cancer stem cells (CSC) profile has been suggested to regulate key steps leading to progression, relapse and metastasis and therefore may be responsible for this otherwise unpredictable heterogeneity. ALCAM, CD133, CD24, LRG5, SOX2, ALDH1A1 have been reported as potential markers for CSC, particularly in digestive system cancer. Aim of our study was to assess the role of these markers in determining clinical outcome for stage III colon cancer patients receiving adjuvant chemotherapy. Methods: Patients undergoing radical surgical resection for stage III colon cancer and receiving adjuvant oxaliplatin in combination with either 5FU or capecitabine were eligible for our analysis. CSC profile (ALCAM, CD133, CD24, LGR5, SOX2, ALDH1A1) was analysed by RT-PCR in primary tumour samples. The multivariate analysis also included adjustments for other variables such as T and N stage, sex, age and tumour location. Results: Seventy-eight patients were eligible for analysis. Only high ALCAM expression was associated with clinical outcome. In particular in colon tumours overexpressing ALCAM we observed a significant interaction for a higher risk of relapse (p = 0.04) and a reduced time to relapse (not reached vs. 33.24 months, HR:0.46, 95%CI:0.23-0.89, p = 0.02). There were no significant differences according to main stratification factors between the high ALCAM group vs. low ALCAM group. In our series N stage (N1 vs. N2-3) resulted also relevant for clinical outcome. Conclusions: Our analysis supports the hypothesis that ALCAM expression may represent a crucial marker for a better risk stratification in stage III colon cancer patients receiving adjuvant chemotherapy. According to our data we also suggest that other potential markers of CSC are probably ineffective for patients stratification. Patients expressing high ALCAM levels may be optimal candidates for therapy intensification and possibly different treatment options.

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Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity

Oncogenesis ◽

10.1038/s41389-021-00373-4 ◽

2021 ◽

Vol 10 (11) ◽

Author(s):

Rida Iftikhar ◽

Harrison M. Penrose ◽

Angelle N. King ◽

Joshua S. Samudre ◽

Morgan E. Collins ◽

...

Keyword(s):

Stem Cells ◽

Colon Cancer ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Progression ◽

Human Colon ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Increased Risk

AbstractObesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LD) utilization, in obesity-driven colonic tumorigenesis. In local colon cancer patients, significantly increased ATGL levels in tumor tissue, compared to controls, were augmented in obese individuals. Elevated ATGL levels in human colon cancer cells (CCC) relative to non-transformed were augmented by an obesity mediator, oleic acid (OA). In CCC and colonospheres, enriched in colon cancer stem cells (CCSC), inhibition of ATGL prevented LDs utilization and inhibited OA-stimulated growth through retinoblastoma-mediated cell cycle arrest. Further, transcriptomic analysis of CCC, with inhibited ATGL, revealed targeted pathways driving tumorigenesis, and high-fat-diet obesity facilitated tumorigenic pathways. Inhibition of ATGL in colonospheres revealed targeted pathways in human colonic tumor crypt base cells (enriched in CCSC) derived from colon cancer patients. In CCC and colonospheres, we validated selected transcripts targeted by ATGL inhibition, some with emerging roles in colonic tumorigeneses (ATG2B, PCK2, PGAM1, SPTLC2, IGFBP1, and ABCC3) and others with established roles (MYC and MUC2). These findings demonstrate obesity-promoted, ATGL-mediated colonic tumorigenesis and establish the therapeutic significance of ATGL in obesity-reinforced colon cancer progression.

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Molecular and biological aspects of forecasting the oncological efficiency of cytoreductive surgery in metastatic colon cancer

Vestnik of Russian military medical Academy ◽

10.17816/brmma73188 ◽

2021 ◽

Vol 23 (3) ◽

pp. 61-66

Author(s):

Aleksey A. Sazonov ◽

Nicolay A. Maistrenko ◽

Pavel N. Romashchenko

Keyword(s):

Stem Cells ◽

Colon Cancer ◽

Surgical Treatment ◽

Cancer Stem Cells ◽

Life Expectancy ◽

Cytoreductive Surgery ◽

Proliferative Activity ◽

Stage Iv ◽

Biological Properties ◽

Metastatic Colon Cancer

Through an immunohistochemical study, the molecular biological properties of adenocarcinoma in patients with stage IV colorectal cancer with synchronous unresectable liver metastases, who underwent cytoreductive interventions for volume removal of the primary tumor, were examined. This study clarified the criteria for selecting patients with stage IV colon cancer with unresectable synchronous metastases in the liver for cytoreductive surgery from the standpoint of the molecular biological properties of the tumor. The prognostic significance of immunohistochemical markers such as the index of proliferative activity of stem cancer cells (ALDH + Ki-67 +) and the receptor for chemokines CXCR4 was established. The level of their expression correlates with the life expectancy of patients who underwent cytoreductive surgery. Thus, the high proliferative activity of cancer stem cells (ALDH + Ki67 + 50%) and the high expression of chemokine receptor (CXCR4 70%) correlate with the rapid disease progression after surgical treatment. A significant inverse relationship was traced between the expression level of the receptor for chemokine CXCR4 as well as the proliferative activity of cancer stem cells and life expectancy of patients with stage IV colon cancer after cytoreductive surgery. The expediency of immunohistochemical studies in patients with metastatic colon cancer has been substantiated. Its implementation provides important information about the potential for tumor aggressiveness, which makes it possible to clarify the indications for performing cytoreductive surgery and improve the results of surgical treatment of this category of patients.

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Tumor Initiating Cells and Chemoresistance: Which Is the Best Strategy to Target Colon Cancer Stem Cells?

BioMed Research International ◽

10.1155/2014/859871 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 25

Author(s):

Emanuela Paldino ◽

Valentina Tesori ◽

Patrizia Casalbore ◽

Antonio Gasbarrini ◽

Maria Ausiliatrice Puglisi

Keyword(s):

Stem Cells ◽

Colon Cancer ◽

Cancer Stem Cells ◽

Anticancer Agents ◽

Cancer Biology ◽

Residual Disease ◽

Aerobic Glycolysis ◽

Cell Subpopulation ◽

Metastatic Colon Cancer ◽

Tumor Initiating Cells

There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called “cancer stem cells” (CSCs). In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics.

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Notch Activation Modulates Bevacizumab Activity by CD44 Positive Cancer Stem Cells in Advanced Colon Cancer

Journal of Molecular Biomarkers & Diagnosis ◽

10.4172/2155-9929.s2-036 ◽

2017 ◽

Vol 01 (S2) ◽

Author(s):

Negri FV ◽

Bozzetti C ◽

Pedrazzi G ◽

Azzoni C ◽

Bottarelli L ◽

...

Keyword(s):

Stem Cells ◽

Colon Cancer ◽

Cancer Stem Cells ◽

Advanced Colon Cancer ◽

Notch Activation

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CD133/CD166/Ki-67 Triple Immunouorescence Assessment for Putative Cancer Stem Cells in Colon Carcinoma*

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.232.cm1 ◽

2014 ◽

Vol 23 (2) ◽

pp. 161-170 ◽

Cited By ~ 14

Author(s):

Claudiu Margaritescu ◽

Daniel Pirici ◽

Irina Cherciu ◽

Alexandru Barbalan ◽

Tatiana Cârtâna ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Colon Cancer ◽

Cancer Stem Cells ◽

Colon Carcinoma ◽

Sodium Dodecyl ◽

High Grade Dysplasia ◽

Early Event ◽

Low Grade ◽

High Grade

Background & Aims: Colorectal cancer represents the third most common malignancy and the fourth most common cause of cancer death worldwide. The existence of drug-resistant colon cancer stem cells is thought to be one of the most important reasons behind treatment failure in colon cancer, their existence putatively leading to metastasis and recurrences. The aim of our study was to investigate the immunoexpression patterns of CD133 and CD166 in colon carcinoma, both individually and in combination, assessing their significance as prognostic markers.Methods. A total of 45 retrospective colon adenocarcinoma cases were investigated by enzymatic and multiple fluorescence immunohistochemistry for their CD133 and CD166 expression and colocalization.Results. Both CD133 and CD166 were expressed to different extents in all cancer specimens, with apredominant cytoplasmic pattern for CD133 and a more obvious membranous-like pattern for CD166.Overall, when comparing their reactivity for the tumoral tissue, CD166 expression areas seemed to be smaller than those of CD133. However, there was a direct correlation between CD133 and CD166 expression levels throughout the entire spectrum of lesions, with higher values for dysplastic lesions. Colocalization of CD133/ CD166 was obvious at the level of cells membranes, with higher coeficients in high grade dysplasia, followed by well and moderate differentiated tumours.Conclusions. CD133/CD166 colocalization is an early event occurring in colon tumorigenesis, with thehighest coeficients recorded for patients with high grade dysplasia, followed by well differentiated tumours. Thus, we consider that the coexpression of these two markers could be useful for further prognostic andtherapeutically stratification of patients with colon cancer.Abbreviations: AJCC - American Joint Committee on Cancer; CCD - charge-coupled device camera sensor; CD133 - prominin-1 (PROM1); CD166 - Activated Leukocyte Cell Adhesion Molecule (ALCAM); CRC - colorectal cancer; CSC - cancer stem cells; DAB - 3,3'-diaminobenzidine chromogen; DAPI - 4',6-diamidino- 2-phenylindole; HE - Hematoxylin and eosin staining; HGD - high grade dysplasia; HRP - horseradish peroxidase; LGD - low grade dysplasia; SDS - sodium dodecyl sulfate*Part of this work has been accepted as a poster presentation at the Digestive Disease Week (DDW) meeting, Chicago, IL, USA May 3-6, 2014

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