Biomedical Engineering Reference
In-Depth Information
the clinic. Homer Pearce (once head of cancer research and clinical
investigation at Eli Lilly and Company) said, ''If you look at the millions
and millions and millions of mice that have been cured, and you compare that
to the relative success, or lack thereof, that we've achieved in the treatment of
metastatic disease clinically, you realize that there just has to be something
wrong with those models''.
57
In the clinic, the normal procedure for humans is
surgery and chemotherapy. If the patient cannot receive surgery or if normal
chemotherapy fails, then nanomedicine is used as a last resort. At this point the
tumor is considered very aggressive and resistant; however, the same cannot be
said of the tumors that are cured in many mice models.
Some of the disparity is present in the methods used to grow the tumors in
animal models. The rate and size of tumor growth in animal models is not
representative of clinical cancers. Clinical tumors have many years to undergo
genetic mutations, slow growth, and evasion of the immune system.
58
While
mouse models can be controlled to develop cancers in a random nature and on
a more representative timescale, for convenience and efficiency, many mouse
models form tumors approximately 10 days following inoculation.
59,60
Still,
mice have a higher rate of metabolism that will result in faster tumor growth
and requires a more frequent dosing regimen as a countermeasure.
Additionally, the ratio of tumor to body weight is also much larger in mouse
models compared to human patients. Having a large tumor mass may
contribute to lower pH and an increased EPR effect for mouse models. Also,
study animals are sacrificed post-treatment to ascertain the extent of the
treatment and if the treatment is positive. When the animal is sacrificed, there
is no chance to check for tumor relapse. The environment where the tumor
grows will influence results as well. Unfortunately, mouse models are not
always orthotropic. Breast cancer cells injected to grow a tumor in the hind
quarters of a mouse will not accurately portray what a tumor in breast tissue
will do. Furthermore, since most murine tumors are xenografts, they need to
be placed in immunodeficient mice. Tumors grown in immunodeficient mice
are less aggressive than tumors that are grown in immunocompetent mice. The
process of immunoediting explains how the immune system can drive the
progression of a tumor to a more resistant and aggressive state. Studies have
shown that tumor formation is much more likely when the cancer cell line
comes from a tumor grown in an immunocompetent mouse.
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While the immune system provides a great example of targeted cancer
therapy, the cancer is still able to escape and continue growing.
62,63
Immune
evasion has become an emerging hallmark of cancer and is made possible by
the heterogeneity inherent in cancer.
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Understanding how cancer resists the
immune system may lead to improved therapeutics in the future.
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1.3.2.1 Cancer is Heterogeneous
There is both intertumoral and intratumoral heterogeneity, with differences in
the cancer type, environment, individual cells, and signaling. Ovarian cancer is
