Topic:Tumor Microenvironment
Subject:Engineering
Volume: 7 pages
Type: Research paper
Style: MLA
Description
Project 1: Tumor Microenvironment Proposal Announcement
Background: Research on tumor-host interactions collectively reveals that: (a) tumors are not
masses of autonomous cells, but function like organs composed of many interdependent cell types
that contribute to tumor development and metastasis; (b) the interactions between the tumors and
their microenvironments are bidirectional and dynamic; and (c) the tumor and its stroma co-evolve
during tumor initiation and progression. The microenvironment is known to be composed of
stromal cells that include fibroblasts, immune and inflammatory cells, adipocytes, glial cells,
smooth muscle cells, and resident and recruited vascular cells. Additional components are: the
extracellular matrix, growth factors/cytokines, and other proteins produced locally and/or
systemically. Microbial flora may also be present in the tumor microenvironment.
The microenvironment can exert both stimulatory and inhibitory influences on
proliferation and malignant properties of tumor cells. For example, the negative influence is
demonstrated in mouse embryos containing teratocarcinoma cells. In this model, the malignant
potential of the tumor cells is restrained by the stromal environment, resulting in cancer-free adult
mice. Conversely, numerous examples document the involvement of stroma in pro-neoplastic
effects. Stromal changes play roles in inflammation, which stimulates tumor cell proliferation,
angiogenesis, invasion, and metastasis which are mediated by cytokines and proteases; and the
interaction of host immune cells with the tumor vasculature, which facilitates metastasis. Stromal
cells can also influence organ-specific metastasis as evidenced by the role of stromal-derived
chemokines and growth factors in metastasis to bone originating from breast and prostate cancers
and multiple myeloma. Finally, an interaction of bone marrow stromal cells with multiple
myeloma cells has been shown to contribute to the development of drug resistance.
Evidence is steadily emerging that critical stromal elements of the tumor are attractive
targets for cancer prevention, because they primarily influence tumor cells in the early stages of
tumor progression. As targets for therapy, cells in stromal elements of the tumor are less likely to
be genetically unstable than tumor cells and are therefore probably less susceptible to the
emergence of drug resistance. Manipulating host-tumor interactions and matrix mechanics has the
potential to reverse the malignant phenotype and reestablish normal control mechanisms. Recent
evidence indicates that stromal cells co-evolve at the earliest onset of cancer, as indicated by
genetic or epigenetic changes in stroma, and these changes can specifically be targeted for
therapy. For example, in patients with multiple myeloma, targeting bone marrow stroma with a
proteasome inhibitor may attenuate bone metastasis. In addition, the development of antiangiogenic
drugs (and thalidomide) demonstrates the anti-tumor efficacy of targeting host
endothelial cells.
Objective: A comprehensive understanding of the tumor microenvironment, including stromal
composition, cell-cell and cell-matrix interactions, and abnormal physiology, as well as cellular
characteristics and mechanics of heterogeneous tumors is key to elucidating the complexities of
cancer. Understanding the cellular, molecular, biochemical, and biomechanical interactions of
tumors within their microenvironment is essential to improving cancer diagnosis and treatment.
Based on what you have learned in class, your interest, and the literature, propose a study which
includes aims, hypothesis, and your proposed approaches to development of novel technologies
and model systems for the study of the tumor microenvironment. The proposal should be limited
to no more than 7 pages with 1 inch margins at 12 point times new roman font. You will also be
required to give your pitch to investors during class on March 27 and full proposal is due March
29. The proposal approaches can include but are not limited to:
Development of novel in vitro 3-dimensional matrix reconstitution and organotypic models
or animal models,
Development of computational and mathematical models
Creation of dynamic and real-time in vitro and/or in vivo imaging techniques suitable for
visualizing molecules, cells, and tumors
The proposed computational models, experimental systems, and/or imaging techniques can be
utilized to look at various factors of the tumor microenvironment such as:
Characterization of the functions of and interactions among the component cells, matrix
molecules, and mechanics in normal organ and tumor-associated stroma, including:
a) identifying all of the cell types present in the stroma, and their functional roles; and
b) identifying the matrix molecules present in the stroma, and the critical soluble
molecules, such as growth factors, cytokines, and chemokines:
c) identifying key matrix mechanics and/or forces and flows that control tumor
progression, metastasis, or drug transport
Characterization of the role of the inflammatory and immune cells and mechanics in the
initiation, progression and metastasis of the tumor, including:
a) identifying inflammatory cells and soluble mediators present in the stroma of different
tumor types, e.g., chemotactic factors responsible for recruiting inflammatory cells;
b) characterizing the effect(s) of inflammatory mediators and mechanics on preneoplastic
stroma in situations where tumors develop in the setting of chronic inflammation;
c) delineating the role(s) of host-pathogen interactions and mechanics in the development
and maintenance of inflammation and/or adaptive immune responses in cancers that
are associated with microbes;
d) elucidating the role(s) of inflammatory cells during invasion, migration, and metastasis;
e) characterizing the hematopoietic network(s) that regulate(s) tumor cell exit,
extravasation, hematogeneous survival, and/or growth at distant sites;
f) determining if immune cells in the stroma are tumor-specific, and characterizing their
potential(s) as antitumor effectors;
g) determining the physiologic properties and mechanical cues of cancer development that
are regulated by immune cells; and
h) characterizing influences of the stromal microenvironment on initiation of antitumor
immune responses and on the interplay between immune effectors and tumor cells.
Identification of alterations in the microenvironment which are critical for tumor
development, progression, and metastasis, and elucidation of the mechanisms responsible
for these changes, including:
a) ‘mapping’ at the cellular and molecular levels the evolution of stroma and matrix
mechanics in experimental models of tumor progression and metastasis and compare
such patterns with changes that occur in human tumors;
b) Characterizing tumor dependence on stroma, strategies to exploit such dependence in
therapy, and mechanisms progressing cancers reduce their reliance on stroma;
c) Exploring if tumor promoters affect the stroma at the cellular and molecular levels
d) Determining role(s) stroma plays in metastatic spread via the blood and/or lymphatics;
e) Characterizing differences between the microenvironment and mechanics of a primary
tumor and metastases
f) Exploring the role(s) of the stromal compartment and mechanics in resistance to drugs
and other treatment modalities.
