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Page 2 of 14 Stenina-Adognravi et al. Vessel Plus 2018;2:30 I http://dx.doi.org/10.20517/2574-1209.2018.40

events that lead to changes in cancer cell differentiation, proliferation, and apoptosis, all of which initiate
uncontrolled growth and spreading. The roles of immunity and of the response of the whole organism
to cancer cells have been historically appreciated, but the role of the microenvironment in the initiation,
progression, and spreading of cancer has become a more active field of study only recently. It has been
[1,2]
accepted that cancer cells are constantly forming in a healthy body but they do not survive. They
may remain dormant for years due to the healthy microenvironment, which does not support the tumor
growth. The tumor microenvironment, which prevents or promotes cancer growth, consists of stromal and
vascular cells, immune and inflammatory cells. Additionally, the extracellular matrix (ECM) and secreted
[3,4]
signals that these cells generate promote or restrict cancer cell division and migration . The progression
of cancer depends on the complex interplay between the tumor cells and the tumor microenvironment.
Targeting the components of the tumor microenvironment is now a recognized powerful tool of cancer
therapy and prevention of spreading and recurrence.

The development of tumor vasculature depends on angiogenesis, accompanied by inflammation, which
is an important factor in predicting tumor vascularization, growth, and spreading. Targeting the
[5]
tumor vasculature has been an active approach in finding new therapeutic targets for many years but,
unfortunately, has not fulfilled the expectations of cancer therapies due to significant side effects and
[6]
adverse events in tumors in response to hypoxia . It has become clear that we have a limited appreciation
of pathological processes associated with the tumor microenvironment and, as a result, inadequate
understanding of potential therapies that may improve the microenvironment and restrict tumor growth.

Tumor angiogenesis and the recruitment of immune and inflammatory cells into the tumor rely on the
[7]
composition of ECM . One important event that occurs during tumor progression is the stiffening of the
ECM, caused by the deposition of collagen and fibronectin, leading to increased proliferation and tumor
advancement . Cancer-associated fibroblasts are important contributors of ECM stiffening . Tumor ECM
[8]
[9]
is also modified by vascular and blood cells that release proteases and chemoattractants and deposit ECM
[10]
to promote angiogenesis, additional recruitment of vascular and inflammatory cells, and inflammation .
[11]
Tumor inflammation is closely associated with the tumor aggressiveness and metastasis . Activated
cancer and vascular cells produce chemoattractants and pro-inflammatory signals to recruit inflammatory
cells from blood. The accumulation of inflammatory cells in a tumor is an important prognostic index
that has been successfully used to evaluate the aggressiveness of cancer in conjunction with other
indexes that describe the proliferation rate of cancer cells and their migratory potential. CD68, a marker
of macrophages is one of the 16 markers evaluated in Oncotype DX, a clinical test that is used to make
therapeutic decisions and predict the aggressiveness of breast cancer [12,13] . The recruitment and retention of
[14]
inflammatory cells in tumors depends on the ECM composition .

This article reviews the contribution of thrombospondins (TSPs), a family of secreted ECM proteins, in
regulation of the cancer microenvironment and the initiation and progression of tumor growth that is
defined by the vascular and ECM remodeling and inflammatory response. It is becoming clear that TSPs
affect every pathological process associated with cancer advancement and are key protein regulators of the
tissue remodeling that occurs with cancer growth.

TSPS AND CANCER
The ECM is complex and ever-changing. All the cells in a tumor constantly remodel the ECM and deposit
growth factors, proteases, pro-inflammatory and chemoattractant proteins into ECM. The composition of
ECM defines whether it will support cancer growth, angiogenesis, and inflammation by providing specific
growth- and migration-promoting signals and changing the physical properties of the tissue. ECM con-
tains structural components, e.g., collagens, and secreted proteins that define the interactions of the cells