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Page 2 of 9 Felton et al. J Cancer Metastasis Treat 2018;4:51 I http://dx.doi.org/10.20517/2394-4722.2018.39

xenografts in the distal mouse colon. The new approach of injecting cells into the distal colon wall results in a pattern
of colon cancer development that closely mimics the progression of metastatic colon cancer in humans. This novel
model of colon neoplasia has great potential for exploring anatomical differences in colon cancer and testing novel
therapeutics.

Keywords: Colorectal cancer, orthotopic tumor model, mouse model, HT-29 cells, colon

INTRODUCTION
In developed countries, colorectal cancer (CRC) is the second most common cause of cancer-related death in
[1]
men and the third in women . Metastatic cancer is the chief reason for CRC-related death; primary tumors
[1]
without metastases are readily cured by endoscopic or surgical therapy . Intriguingly, strong evidence re-
[2-6]
veals important differences between cancers in the proximal vs. distal colon .
Compared to cancers of the distal colon, proximal colon cancers are more common in women, are associat-
ed with microsatellite instability and the serrated pathway, and are more likely to be at advanced stages when
first diagnosed. Distal colon tumors are more likely to be associated with chromosomal instability and arise
[6]
from the pathway involving dysregulated APC, K-ras, DCC, and p53 . Previous studies reported conflicting
findings with regards to whether mortality was significantly different in those with primary right- vs. left-
[7-9]
sided colon cancer . A meta-analysis found higher mortality in patients with right-sided compared to left-
[7]
sided colon cancer . A recent database study found that right-sided colon cancer was associated with lower
cancer-specific mortality at the localization stage, equivalent mortality at the regional stage, and higher mor-
[7]
tality at the metastatic stage . Another recent retrospective study found those with left-sided colon cancer
[10]
had better survival outcomes, especially with stage III cancers . From 1998 to 2013, the SEER (Surveillance,
Epidemiology, and End Results) database identified 90,635 and 112,679 persons diagnosed with left- and
[7]
right-sided colon cancer, respectively .
Few therapeutics are either effective or available to treat persons with metastases to the liver and other or-
gans. To improve therapeutic outcomes, there is great urgency to gain a better understanding of the mecha-
nisms underlying colon cancer dissemination as a basis to develop targeted therapies. For investigators to
test such new therapeutics with some degree of reliably there is also a great need to conceive and develop
novel models that more closely mimic human disease.

Several animal models of metastatic colon cancer are available, with varying degrees of reproducibility,
limitations, and imperfect fidelity to the biology of human cancer. Current murine models are limited by
location, depending on what model is used, and cancers in different locations have different genetic profiles.
A case in point is ApcMin mouse models that were meant to recapitulate defective Wnt/β-catenin signaling
[11]
present in ~90% of human colon cancer ; in the most commonly used ApcMin mouse strains, tumors are
almost uniformly adenomas, not adenocarcinomas, and are located predominantly in the small intestine,
not colon. Also, murine models using injection of human colon cancer cells are limited by the need to use
[12]
immune-deficient mice to allow tumors to develop, thus excluding the testing of immunotherapies . None-
theless, using syngeneic models with murine colon cancer cells is also imperfect because these cell lines are
[12]
less well-studied and their biology may not mimic that of human cancers .
Despite their limitations, murine models have long served as the most reliable platform for preclinical evalu-
[12]
ation of new drugs and technologies . These include models employing chemical carcinogenesis, genetic
engineering, and animal- or patient-derived xenografts [1,13] ; the latter have been particularly helpful to study
the mechanisms underlying the metastatic spread of human colon cancer and identify susceptible therapeu-
tic targets [1,12] . Colorectal cancer xenografts grown subcutaneously in immunodeficient mice are limited by
the lack of metastasis; instead, orthotopic tumor models involving injection of CRC tumor cells or implanta-