Page 59 - Read Online

Page 2 of 11 Narayanan et al. J Cancer Metastasis Treat 2019;5:36 I http://dx.doi.org/10.20517/2394-4722.2018.77

Conclusion: These finding suggests the CSCs within LMCA maybe a novel therapeutic target by manipulation of the RAS.

Keywords: Cancer stem cells, colorectal, colon, cancer, adenocarcinoma, liver, metastasis, renin-angiotensin system

INTRODUCTION
Colorectal cancer (CRC) accounts for 9.7% of all cancers with approximately 1.5 million cases worldwide in
[2]
[1]
2015 , including 3158 cases in New Zealand . It is the second most common cause of cancer death in the
[2]
[3]
United Kingdom and New Zealand .
The pathogenesis of CRC relates to a complex interaction between genetic predisposition and lifestyle
[1]
factors . There are hereditary and non-hereditary CRC sub-types, although the majority are sporadic
[1]
and result from somatic mutation in response to environmental factors . A key molecular pathway in the
development of about 80% of CRC cases is the adenocarcinoma sequence, in which an accumulation of
[4]
genetic mutations, particularly in the adenomatous polyposis coli pathway leads to carcinogenesis . Diets
high in animal fat and red meat, physical inactivity and excess body weight, heavy alcohol consumption and
[5]
smoking are known modifiable risk factors for CRC .
The liver is commonly the first metastatic site for CRC, and may be the only site of spread in up to 30%-40%
[6]
of patients with advanced disease . 20%-25% of CRC patients have detectable synchronous liver metastases
at the time of diagnosis, and another 40%-50% of patients will subsequently develop metachronous liver
[7]
metastasis within three years of resection of the primary tumor .

The current concept of CRC proposes that the primary mode of tumor spread is via the portal system, and
[6]
hence resection of isolated liver metastasis from CRC adenocarcinoma may be curative . However, the
[8]
observation of circulating CRC cancer stem cells (CSCs) infers that the assumption of the liver being the
most suitable site for metastasis remains to be determined. The median survival of liver metastasis from
CRC adenocarcinoma without treatment is less than 12 months from presentation, with improved prognosis
[9]
for patients with isolated liver metastasis . Approximately 20%-30% of patients with liver metastasis from
[10]
CRC adenocarcinoma have disease confined to the liver and is therefore potentially operable with a five-
year survival of 25%-44% [7,11] . There has been recent focus on pre-operative neo-adjuvant chemotherapy to
improve disease-free and overall survival by downsizing metastatic liver disease to increase operability and
[12]
treat systemic disease .
The CSC concept of cancer proposes that a subpopulation of cells within a cancer that possesses the
properties of embryonic stem cells (ESCs) are the driving force for carcinogenesis due to their innate ability
[13]
to promote angiogenesis, local invasion, distant metastasis, and resistance to apoptosis . Although the
origin of CSCs remains to be elucidated, they are distinguishable from the cancer cell population by their
expression of ESC markers, well researched in many cancer types including oral cavity squamous cell
[17]
carcinoma (OCSCC) affecting different sub-sites [14-16] and glioblastoma (GB) . Increased expression of
[18]
ESC markers has been associated with increased tumor size, local invasion and metastasis , worsening
[20]
[19]
prognosis, treatment resistance and risk of local recurrence or metastasis .
We have recently demonstrated the presence of three CSC subpopulations within liver metastasis from colon
+
+
adenocarcinoma (LMCA): a SOX2 /NANOG /KLF4 /c-MYC /OCT subpopulation within the tumor nests
-
+
+
+
+
+
+
-
+
+
+
(TNs), and a SOX2 /NANOG /KLF4 /c-MYC /OCT4 CSC subpopulation and a SOX2 /NANOG /KLF4 /
[21]
+
c-MYC /OCT CSC subpopulation within the peri-tumoral stroma (PTS) .
+
The renin-angiotensin system (RAS) is a hormonal system that is classically known for regulation of
[22]
cardiovascular homeostasis and blood pressure . A key component of the RAS is angiotensinogen which