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Stenina-Adognravi et al. Vessel Plus 2018;2:30 I http://dx.doi.org/10.20517/2574-1209.2018.40 Page 5 of 14
as a part of this program, which initiates anti-cancer defense in multiple body systems. For example,
increased proliferation of cancer cells due to TSP-1 signaling may render the cancer cells more susceptible
[79]
to the elimination by natural killer cells . Furthermore, TSP-1 signaling may facilitate activation of p53, a
regulator of apoptosis [80,81] . Promoting cancer cell proliferation and invasion may result in better responses
from T-cells due to expression of cancer-specific antigens and their circulation in blood. Similar to the
therapeutic approaches designed by humans, e.g., chemotherapy and radiation treatment of cancers, the
natural body responses may be the most efficient when the cancer cells are rapidly growing. Understanding
why TSPs have cell-specific responses and seemingly contradictory effects would explain how they protect
from cancers in the case of TSP-1 or promote cancer growth in the case of TSP-4. Better understanding
these complex and sometimes contradictory properties of TSPs will only be possible by developing an
integrative approach and more holistic view of the pathological and physiological processes regulated by
these proteins, considering the fact that they affect multiple organ systems.

Newly developed integrative approaches to cancer therapies have pushed the field to better understand
the causes of cancer and the mechanisms, by which tumors grow and spread. As a result, inflammation
and the metabolic changes have become the focus of many studies that investigate how the cancer
microenvironment is regulated [82,83] . A growing body of evidence connects increased levels of blood glucose
and insulin and chronic inflammation with cancer initiation and progression [84,85] . While the association
of diabetes and cancer has been known for many years [86-89] , recent studies suggested that even post-
prandial elevations in blood glucose and/or insulin increases the risk of cancer. The glycemic load (GL, a
measure of the increase in post-prandial blood glucose caused by food) and/or the high dietary glycemic
index (GI, another index that estimates the effect of foods on post-prandial blood glucose) were associated
[95]
with a risk of breast cancer [90-94] ; with lung cancer ; prostate cancer [93,96] , especially with its aggressive
[93]
[97]
form ; endometrial cancer [93,98] ; ovarian cancer ; and digestive tract cancers (esophageal, stomach,
colorectal, liver, gallbladder, and pancreatic) [93,96,99-103] . The emerging evidence stresses the importance of
diets low in GI and GL and reduction of carbohydrates in diets as a part of healthy nutrition and lifestyle
to prevent cancer development and recurrence [104-106] . The connection between chronic inflammation and
cancer has been known for a long time: e.g., an association between the hepatitis and the liver cancer
has been well recognized and studied [107,108] , the existence of cancers caused by pancreatitis and Crohn’s
disease has been known and accepted [109,110] , and the connection between the infection with italicize and
stomach cancer has been confirmed [111,112] . Diabetes, pre-diabetes, and metabolic syndrome are associated
with chronic inflammation [113-116] and can be induced by the chronic inflammation in growing adipose
tissue [117-119] and pancreas [120-122] . Thus, metabolic dysfunction appears to increase the risk of cancer directly
(due to an increased blood glucose and insulin) and by increasing the inflammation. TSP-1, that normally
restrains angiogenesis and prevents the growth of a tumor, is downregulated by high blood glucose levels
in many tissues [123,124] , thus, providing a link between the elevated blood glucose and cancer. TSP-1 has
[124]
been shown to be downregulated by a microRNA, miR-467, in response to hyperglycemia . Inhibition
of miR-467 using an antagonist effectively inhibited hyperglycemia-induced breast cancer growth in
mice [125] . Furthermore, decreased levels of TSP-1 are associated with higher inflammation in tissues,
probably due to its ability to stimulate phagocytosis in macrophages and to promote the resolution of
inflammation [66,126] . Therefore, increasing the levels of TSP-1 may stop or prevent the growth of tumors in
multiple complementary ways by decreasing cancer angiogenesis and promoting the resolution of cancer
inflammation.

ANTI-CANCER TSP-BASED APPROACHES
The functions of TSP-2, TSP-3, and TSP-4 in regulation of cancer growth are not well enough understood
to identify potential therapeutic approaches based on the regulation of expression of these proteins or on
their specific ligands and cell surface receptors. However, TSP-1, a TSP family member discovered and pu-
rified from platelets 40 years ago, has been a target for developing strategies to modulate its levels or to
[127]