cancer.pdf

3855
Abstract. – This is a review regarding differ-
ent types of cancer treatments. We aimed at an-
alyzing the tumor microenvironment and the re-
cent trends for the therapeutic applications and
effectiveness for several kinds of cancers.
Traditionally the cancer treatment was based
on the neoplastic cells. Methods such as sur-
gery, radiation, chemotherapy, and immunother-
apy, which were targeted on the highly prolifer-
ating mutated tumor cells, have been investigat-
ed. The tumor microenvironment describes the
non-cancerous cells in the tumor and has en-
abled to investigate the behavior and response
of the cancer cells to a treatment process; it
consists in a tissue that may have a predictive
significance for tumor behavior and response
to therapy. These include fibroblasts, immune
cells and cells that comprise the blood vessels.
It also includes the proteins produced by all of
the cells present in the tumor that support the
growth of the cancer cells.
By monitoring changes in the tumor microen-
vironment using its molecular and cellular pro-
files as the tumor progresses will be vital for
identifying cell or protein targets for the cancer
prevention and its therapeutic purposes.
Key Words:
Cancer, Tumor, Tissue microenvironment, Thera-
peutic applications.
Introduction
Cancer is one of the major causes of death glob-
ally. More than 11 million people are diagnosed
with cancer and this rate has been estimated to
increase to 16 million by 2020. In 2017, nearly
13% of all cancers diagnosed in adults ageing 20
and older were rare cancers, defined in this report
as cancers with fewer than 6 cases per 100,000
people per year1
. An early detection and treatment
of the cancer for a better health management are
needed. The cancer evaluation is carried out cov-
ering the nature of cancer, risk assessment, pre-
vention, and health management2
. A tumor is an
abnormal growth of cells that have no functional
purposes and the potential to spread to the adjoin-
ing cells or organs or other parts of the body. Not
all tumors are cancerous; indeed, benign tumors
do not spread to other parts of the body3-5
. There
are many types of cancers that affect the humans6
and the cancer cells show no signs or symptoms
at an early stage of development. The causes of
the benign tumor are not very clear and they
may be due to reasons such as genetic disorders,
unhealthy food habits, occupational stress, expo-
sure to radiations and/or intake of toxins, may
be caused by infections or inflammations, etc..
Generally benign tumors do not require treatment
or removal. If there is a recommended treatment,
the tumor is removed by surgical procedures. The
surgical procedure to remove the tumor should
not damage the surrounding healthy cells or
tissues. The non-surgical procedure commonly
followed is medication or by a measured quantity
of radiation. Tumor shows signs of symptoms
as it starts to grow in mass. Symptoms of the
growth of the tumor are related to the location
where they are growing. The common types of
benign tumors are adenomas, fibroids, hemangi-
omas, lipomas, meningiomas, myomas, nevi or
moles, neuromas, osteochondromas, papilloma,
etc.7
. The common local symptoms of cancer may
be due to the growth of the mass of the tumor or
its process of ulceration. The growth of the mass
in the brain may affect the normal functioning of
the brain, the growth of a mass in the lungs can
European Review for Medical and Pharmacological Sciences 2018; 22: 3855-3864
J.-J. WANG1
, K.-F. LEI2
, F. HAN3
1
Department of General Surgery, Chun’an First People’s Hospital, (Zhejiang Provincial People’s
Hospital Chun’an Branch), Hangzhou, Zhejiang Province, China
2
Department of General Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of
Hangzhou Medical College, Hangzhou, Zhejiang Province, China
3
Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of
Hangzhou Medical College, Hangzhou, Zhejiang Province, China
Corresponding Author: Fang Han, Ph.D; e-mail: 25852832@qq.com
Tumor microenvironment: recent advances in
various cancer treatments

J.-J. Wang, K.-F. Lei, F. Han
3856
cause blocks in the bronchus, leading to various
respiratory disorders. The growth of a mass in
the breast tissues can lead to breast cancer and
the lump can be easily felt. The ulceration of the
mass leads to bleeding of the tumor and based on
the location shows up various symptoms at vari-
ous stages of the abnormalities. The growth of the
masses with the ulcerations may be painless at
times and the individual may feel the pain at the
advanced stage of cancer8
. The systemic symp-
toms of the tumor occur due to the effects that
are unrelated to direct or metastatic spread. The
commonly observed symptoms are unexplained
weight loss; fever, feeling fatigue, skin condition
changes, etc.. The metastasis form of cancer
spreads from its original growth position to the
near by locations by spreading to the adjoining
cells or tissues, lymphatic spread to regional
lymph nodes or by hematogenous spread via the
blood to the various parts of the body9
.
Treatment for Cancer
There are many types of cancer treatment
methods depending on the type of cancer and at
what stage it is advanced. There is no particular
method or technique foe treatment for cancer.
Treatment options can be chemotherapy, surgery,
radiation therapy, hormonal therapy, targeted
therapy including immunotherapy, etc.. In some
cases the treatment plan may use a combination
of the treatment methods to have maximum ef-
fectives for the treatment. Each of the treatments
has its own side effects to the patient; then, it is
always necessary for the doctor to discuss the
treatment plans with the patient and their family
and obtain their concurrence before proceeding
with the treatment plan. In some cases, it is al-
ways safe for the patient and the doctor to go
in for a second opinion for proceeding with any
treatment plan. A complete removal of the cancer
tissues without causing damages to the adjoining
tissues is the required goal for any treatment plan.
The complete of removal of the cancer tissues is
limited by property of the cancer tissues to spread
to the adjoining tissues or spread to distant sites
by microscopic metastasis. Treatment procedures
such as chemotherapy and radiotherapy have neg-
ative side effects on the normal healthy tissues.
The basic purpose of a cancer treatment plan is
to have cure for the cancer and, when a complete
cure is not possible, the treatment plan should be
to suppress the cancer to a subclinical state and
maintaining the normal state for the subject to
lead a normal quality of life.
Types of Cancer Treatments
With the technological advances the cancer
treatments have undergone tremendous changes
and the understanding of the underlying biolog-
ical processes have increased. Various cancer
treatment methods have been practiced in the past
and many innovative methods, such as target-
ed therapy, are being practiced currently. Since
new information and understanding of biological
process of cancer tissues are emerging regularly,
new treatment procedures and plans are being
developed and modified to have increased effec-
tiveness and precision of the treatment, thereby
enabling the survivability of the patients and im-
proving their quality of life. Cancer can be treat-
ed by surgery, chemotherapy, ionizing radiation
therapy, hormonal therapy, targeted therapy etc.
Surgery
Treatment of cancer by surgical procedure is
commonly practiced for non-hematological can-
cers. By surgical method, the surgeon removes
the cancer tissues from the body. The surgical
procedure can give a complete or partial cure
for the cancer. There may be side effects of the
surgical procedure depending on the type of
cancer and the health condition of the individual.
If the cancer has metastasized to other parts of
the body, then removal of cancer completely by
surgical process is not possible. The growth of the
cancer cells follows the Halstedian model of can-
cer progression10
where the tumors start growing
locally and spreading to the lymph nodes and to
the rest of the body. The treatment of cancer by
surgical procedure can be done to cancers that are
localized and the tumor is of small size.
Some of the cancer treatments by surgical pro-
cedures are mastectomy of breast cancer, brain
tumor by neurosurgery, prostatectomy for pros-
tate cancer, kidney cancer, lung cancer, liver
cancer etc.. Surgically, the aim is to remove the
locally grown tumor or removal of the entire
organ if fully spread to the organ. Cancer cells
cannot be completely removed by the surgical
procedure, and even a presence of a single cancer
cell that is invisible can regrow into a new tumor
and spread to other parts of the body. The chanc-
es of reoccurrence of the cancer can be assessed
by carrying out biopsy by the pathologist; the
surgically removed tissues is analyzed for the
presence of healthy tissues. Evaluating the pres-
ence of healthy or cancerous tissues, the amount
of cancerous tissues left in the patient can be an-
alyzed, which is useful to investigate the staging

Tumor microenvironment: recent advances in various cancer treatments
3857
of cancer11,12
. Other treatment procedures, such as
chemotherapy, can be done before or after that the
surgical procedure is carried out to remove the
affected tissues.
Chemotherapy
The method of chemotherapy is carried out
through the use of drugs, usually known as
anticancer drugs, to kill or destroy the cancer
cells. These drugs interfere with the growth of
tumors and even destroy the cancer cells. The
chemotherapy is generally considered as an ef-
fective method of treatment of cancer; however it
can cause severe side effects as they can destroy
either healthy cells or tissues. The side effects
caused by the chemotherapy treatment depend
upon the type of drugs being used for treatment
and the type of the cancer, its locations and also
on the individual’s response to the particular
chemotherapy treatment. The side effect on the
cancer patient is not related to the effectiveness of
the treatment and it vanishes once the treatment
process is completed. Generally the chemothera-
py treatments are prescribed to a subject in mea-
sured quantity or in a specific number of intervals
over a period of time. Sometimes the chemother-
apy is administered as two or more drugs at the
same time; this method of treatment is known as
combination chemotherapy13
.
Radiation Therapy
Radiation therapy method of cancer treatments
makes use of high doses of radiation generally
ionizing radiation to kill cancer cells and destroy
the tumor tissues. This treatment is commonly
used in conjunction with the surgery to remove or
reduce the size of the tumors. The radiation thera-
py is commonly delivered externally or internally
to the desired location. The radiation therapy giv-
en both internally or externally can also damage
the normal cells and induce the side effects of the
normal cells due to these ionizing radiations14
.
The radiation therapy is commonly used to
treat most of the types of tumor such as cancers
of the brain, breast, cervix, larynx, liver, lung,
pancreas, prostate, skin, stomach, uterus, etc..
Radiation therapy is also used to treat cancers
like leukemia and lymphoma15
. The radiation
dose to be delivered to the cancer or tumor site
depends upon various factors such as age of the
person, type of the tumor, location of the tumor,
and possible side effects on the radiation source
on the nearby tissues and organs. The radiation
therapy is not used if the cancer is at the advanced
stages or if the tumor is located at highly vulner-
able locations. The cancer cells grow and divide
faster than the normal cells. The radiation therapy
uses a specialized equipment to deliver measured
doses of radiation to the cancer cells. The radia-
tion therapy kills tumor cells by damaging their
DNA either directly or by creating free radicals
within the cells that can in turn damage the DNA.
This treatment uses high-energy ionizing radi-
ation such as x-rays. These treatments are com-
monly practiced only on adults and in children
they have significant side effects.
Immunotherapy
Immunotherapy is a method of cancer treat-
ment that helps the immune system to fight
cancer. This is also known as biologic therapy,
which stimulates the disease fighting mechanism
within the patient’s body to fight the cancer. A
high number of researches have been carried out
to treat the cancer by immunotherapy, such as
monoclonal antibodies that block specific protein
function by binding to cancer cells, which train
the immune system to recognize and attack the
cancer cells. This method of treatment is safe and
does not have any major side effects.
Hormone Therapy
The hormone therapy fights cancer by chang-
ing the amount of hormones in the body to treat
certain types of cancer that depend on these
chemicals to grow and spread. This treatment
method is used for treating cancers of breast, re-
productive system and prostrate. The side effects
depend on the type of cancer, age, sex and the
type of drug used in the treatment.
Targeted Therapy
The targeted treatment of cancer targets the
cancel cells that re-enable the cells to grow,
divide and spread. Targeted treatment uses spe-
cific agents for the deregulated proteins of cancer
cells. The small molecule targeted therapy drugs
are generally inhibitors of enzymatic domains on
the mutated, overexpressed, or otherwise critical
proteins within the cancer cells.
Tumor Microenvironment
Tumor Microenvironment (TME) is the cel-
lular environment in which the tumor exists in
the human system. It includes the blood vessels,
fibroblast, cells that contribute to the immunity,
bone marrow-derived inflammatory cells, lym-
phocytes, signaling and the extracellular matrix

3858
(ECM)16,17
. The tumor existing can interact with
the surrounding microenvironment leading to
different effects. The tumor can interact with
the microenvironment by releasing extracellular
signals, can promote tumor angiogenesis and
induce peripheral immunity tolerance. The im-
mune cells in the microenvironment can also
affect the growth and evolution of the cancerous
cells18
. The tumor microenvironment contributes
to the tumor heterogeneity. Tumor microenviron-
ments are recognized as key-contributing factors
for studying the cancer progression and drug
resistance to the cancer treatment. Figure 1 il-
lustrates tumor microenvironment showing the
cell-cell interactions that contribute to cancer cell
progression, invasion and metastasis. The cancer
is not isolated in the environment; instead, it is
due to the collaboration of different types of the
uncontrolled growth of the cells. The cancer cells
also exhibit a characteristic features that are dif-
ferent from that of the healthy tissues, which en-
ables for pharmacological targeting. The cancer
cells are malignant cell masses that can damage
the adjoining cells. The interactions between
the malignant and normal cells create the tumor
microenvironment. The non-malignant cells of
the tumor microenvironment have a dynamic and
often tumor-promoting function at all stages of
carcinogenesis19
. The condition within the tumor
microenvironment has also varying the levels of
metabolic characteristics of tumors and can be
used for planning the treatment20
. The common
features of tumor microenvironments suggest that
targeting the nonmalignant cells, or mediators of
their communication, have applications across
different tumor types that could complement oth-
er treatment options21
. The tumor – to progress
and develop into a life-threatening entity –has to
develop four characteristic features: (a) ability to
move; (b) capability to degrade the extra cellular
matrix (ECM); (c) capability to survive in blood;
(d) capability of establishing itself in a new tissue
environment. The tissue microenvironment is of
critical importance to study the tumor progress
and its development within the tissues22
. The
role of cancer tissue microenvironment during
the growth and the progress stage is of critical
importance for studying and understanding the
cancer tissue biology and will be useful for
diagnostics and therapeutic purposes. The fol-
lowing sections investigate the tumor associated
stroma at the primary sites enable to support the
tumor growths, with a role of vasculature, fibro-
blasts, macrophages, immune suppressor cells
Figure 1. Tumor microenvironment shows the cell-cell interactions, which contribute to cancer cell progression, invasion,
and metastasis.

3859
and various other components of the tumor that
are supportive to the tumor microenvironment.
Most of the cancers are carcinomas or cancers
commonly grow in the epithelial tissues that are
not vascularized23
. The vascular structures of
the tumors are leaky and they accumulate mol-
ecules in the blood stream to a greater extent as
compared to that of the normal tissues. These
have enhanced permeability and retention ef-
fect, and the vasculature of the tumor is gener-
ally leaky, accumulating the molecules in the
blood stream instead of the normal tissues. The
tumor microenvironment is generally hypox-
ic; since the tumor mass increases and grows
further away from the blood vessels leading to
genetic disability, the lack of oxygen can also
cause glycolytic behavior in cells, inducing the
greater cell migration in-vivo and in-vitro. This
may also lead to degradation of the extra cellu-
lar matrix (ECM)24,25
. The reactive stroma cells
of a carcinoma are the connective tissues locat-
ed below the basal lamina, such as fibroblasts,
ECM, cells that are responsible for immunity
and other molecules and cells. The stroma sur-
rounding the tumor often reacts to the intrusion
through the inflammation, similar to the ways
they respond to wounds26
. The inflammation
can enhance the angiogenesis and drastically
increase the cell cycle and prevent cell death
and augment tumor growth27
. Carcinoma asso-
ciated fibroblasts (CAFs) are a heterogeneous
group of fibroblasts whose functionality is tak-
en away by the cancer cells and is redirected to-
wards carcinogenesis28
. CAFs are derived from
normal fibroblasts in the surrounding stroma,
but can also come from pericytes, fibrocytes,
mesenchymal cells, smooth muscle cells, epi-
thelial mesenchymal transition (EMT) or en-
dothelial mesenchymal transition (EndMT)29-31
.
CAFs in vitro do not retard the cancer growth
and perform several functions that support the
tumor growth32
. CAFs also secrete a vascular
endothelial growth factor (VEGF), fibroblast
growth factor (FGFs), platelet derived growth
factor (PGGF) and other pro-angiogenic sig-
nals that will induce the angiogenesis33
. CAFs
also secrete a transforming growth factor beta
(TGF-β) that is associated with EMT and – by
this process – the cancer cells metastasize and
inhibit the cytotoxic T cells and natural killer
T cells34,35
. CAFs restrict the cell distribution
by physically excluding them as medicated by
their cellular matrix and also excluding them
via biosynthesis of CXXL12.
Recent Advances in
The conventional cancer therapy treatments
are effective to the cancer cells but they are also
cause of damage to the healthy tissues and cells.
New treatment methods of cancer treatments are
being practiced for the treatment of cancer and
its molecular mechanisms are well characterized.
The slow or rapid growth of the tumors cells
results in the inability of the blood vessels to
provide oxygenation and nutrients to the tumor
cells, leading to oxygen deficient or hypoxic re-
gions within the tumor. Tumor microenvironment
will enable to investigate the clinical trials tests,
many types of treatment such as new drugs, new
approaches to treatment method using surgery
or a radiation therapy or a new combination of
treatments.
Tumor microenvironment is considered im-
portant for the cancer therapy due to the varying
levels of the influence of the different treatments
methods used. The various drawbacks of the
conventional methods of tumor treatments are
that the tumor vascular structures are leaky and
highly disoriented; they lack of oxygenation to
the tumor core, making it immune to radiation
treatments, since to be delivered, the cells far
from blood vessels required – and not receive –
the necessary nutrients or any chemotherapy sub-
stances. Due to these drawbacks, tumor micro-
environment and an effective therapeutic method
for cancer prognosis and treatment are needed.
Current researches on tumor treatments are fo-
cusing on microenvironment as the treatment ef-
ficiency of the anticancer therapies differs signifi-
cantly in comparison of those found in the normal
tissues. Then, investigations are now focusing on
the tumor microenvironment as a separate can-
cer associated entity that may be targeted. New
methodologies are identified and are effective
through specific targeting of the tumor micro-
environment. The tumor microenvironments are
extensively exploited in the tumor vasculature,
as the oxygen deprives cancer cells, which are
effective to the radiation therapy.
The melanoma patients develop resistance to
both chemotherapy and targeted-therapy drugs.
The chemotherapy and targeted therapies, im-
mune checkpoint blockade treatment methods
commonly practiced, are not effective to all the
melanoma patients. A number of contributing
factors such as gene mutations, the physiology
of the cell functionality and tumor heterogeneity,
contribute to the resistance of the tumor cells

3860
to the treatment provided. Recent investigations
carried out have shown the role of inflammatory
tumor microenvironment. Furthermore, it has
been proven that the multi-modal approach for
targeting the microenvironment, in addition to
malignant cells, is necessary for a better therapy
response36
.
Angiogenesis is a formation of new blood ves-
sels involving the migration, growth and differen-
tiation of endothelial cells that line the inside wall
of the blood vessels, which are controlled by the
chemical signals in the body. Controlling the an-
giogenesis is a critical step in the cancer progres-
sion and its potential therapy. The role of tumor
microenvironment in the control of angiogenesis
and the method of dissection of the molecular in-
teractions enhances the prognostic and facilitates
the targeted therapy37
.
Understanding of the tumor stroma in ad-
vancing cancer is improved by the scaffolding
and matrix-based 3D systems. The drug delivery
systems made from synthetic and natural bioma-
terials deliver drugs to kill stromal cells or repro-
gram the microenvironment for tumor inhibition.
3D models have been used to understand the
tumorigenesis. Also, the effects of tumor stroma
for cancer treatment for different drug delivery
systems were analyzed38
.
Chemoprevention is the use of pharmacologic
or natural agents that inhibit the development of
invasive cancer either by blocking the DNA dam-
age that initiates carcinogenesis or by arresting or
reversing the progression of premalignant cells,
in which such damage has already occurred.
Studies39
of primary dysfunction in the tumor
microenvironment and the epithelial dysfunction
are critical for the carcinogenesis, especially for
the cancer chemoprevention.
Hypoxia tumor cells are resistant to the cancer
therapies and the reasons may be due to the ad-
vanced stages of malignancy. These cells inhibit
tumor cell differentiation and play a direct role in
the maintenance of the cancer stem cells. They
were found to have profound impact on the evo-
lution of the tumor stromal microenvironment.
The hypoxia may enable to create a microenvi-
ronment to differentiate the tumor cells and the
stromal cells, suggesting that targeting hypoxic
stem cells may be a key to successful tumor
management40
.
Tumor cells retain a range of dependence on
interactions with the non-malignant cells and the
stromal elements that constitute the tumor micro-
environment. By understanding the interactions,
the pathogenesis of most B Cell lymphomas, and
their potential therapeutic opportunities for tar-
geting oncogenic pathways, is possible now and
in the future41
.
Studies were carried out to analyze the tem-
poral changes in gene expression when breast
cancer cells survive and grow on brain, bone
marrow, and lung tissue maintained in an in vivo
culture system, as models of the metastatic colo-
nization of these tissues. It was observed that the
transient activation of the genes associated with
homeostasis and stress, later by the elaboration of
cell morphology and cell division, lead the cells
adapted to thrive in the host tissue microenviron-
ment42
.
Breast cancer treatment using the microen-
vironment by targeting the generation of DNA
intercalation inhibits topoisomerase II and inter-
feres with the DNA replication. The chemother-
apeutic agents kill cancer cells and the treatment
triggers a stromal reaction leading to TNF-α
production by endothelial and other stromal cells.
The network of the endothelial-carcinoma my-
eloid signaling interactions provides a mecha-
nism linking chemo-resistance and metastasis
with possibility for intervention43
.
Development of the prostrate cancer is not on-
ly confined to the cancer epithelial cell, but also
involves the tumor microenvironment. Prostate
cancers metastasize to the skeleton, and there is
considerable research being carried out to ana-
lyze the interaction between prostate cancer epi-
thelial cells and the bone microenvironment. The
signaling pathways do exist between epithelial
cells, stromal cells and the extracellular matrix to
support tumor progression from the primary site
to regional lymph nodes and the distant metasta-
ses. The prostate cancers metastasize to the skel-
eton and research is being carried out to study the
interactions between prostrate cancer epithelial
cells and the bone microenvironment. The signal-
ing pathways that are involved in normal prostate
and bone development lead to dysregulation in
cancer, thereby simulating excessive cell growth
and neovascularization and leading to invasive
properties to the epithelial cells, weakening of
the antitumor immunity and castrate-resistant
disease. This study regarding the relationship
between cancer epithelial cells and the organ spe-
cific microenvironment enables the development
of novel therapeutic techniques44
.
Acquired resistance to anticancer treatments
is an essential barrier to reduce the morbidity
and mortality of the malignant tumors. Tissue

3861
microenvironments have been found to influence
cellular phonotypes and to have susceptibility to
toxic insults. The expression of WNT16B in the
prostate tumor microenvironment attenuated the
effects of cytotoxic chemotherapy in vivo, there-
by promoting tumor cell survival and disease
progression. These results delineate a mechanism
by which genotoxic therapies given in a cyclical
manner can enhance subsequent treatment resis-
tance through cell nonautonomous effects that
are contributed by the tumor microenvironment45
.
The bone marrow microenvironment enables
the survival, differentiation, and proliferation of
hematopoietic cells, which are supported by fibro-
blast-like bone marrow stromal cells, osteoblasts,
and osteoclasts, that secrete soluble factors and ex-
tracellular matrix proteins that mediate these func-
tions. This makes the normal hematopoietic cells
and epithelial tumor cells that metastasize to bone,
protect from the chemotherapeutic agents. Due
to this drug resistance, tumor cells are protected
from apoptosis induced by both chemotherapy and
physiologic mediators of cell death, thereby allow-
ing them to survive and lead to minimal residual
disease, increasing the probability for development
of acquired drug resistance46-48
.
Pancreatic cancer is one of the major caus-
es of cancer death in the world. The structural
proteins in the microenvironment of pancreatic
cancer can be modified or targeted, including the
hyaluronan, collagen and secreted protein, acidic
and rich in cysteine. Current methods are being
exploiting rather than targeting/destroying the
microenvironment by normalizing the structur-
al proteins, reversing epithelial-to-mesenchymal
transition. The results have shown beneficial re-
sults that can be clinically evaluated49,50
.
There are three methods commonly used to de-
tect the lung cancers: (1) measurement of partial
oxygen pressure (pO2) with needle electrodes; (2)
detection of hypoxia-induced proteins in tumor
or blood; (3) imaging hypoxia and tumor vascu-
lature49
. Presently, there are several promising
modalities to image hypoxia and the tumor vas-
culature; these include dynamic perfusion imag-
ing and positron emission tomography scanning
with radiolabeled nitroimidazoles. To evaluate
the effects of these agents, a non-invasive mean
of imaging the TME is critical. To date, there are
several promising modalities to image hypoxia
and the tumor vasculature; these include dy-
namic perfusion imaging and positron emission
tomography (PET) scanning with radiolabeled
nitroimidazoles.
Though there are many therapeutic advances
for the cancer treatments, most of the mature
B-cell malignancies remain incurable. Evi-
dence suggests that crosstalk with accessory
stromal cells in specialized tissue microenvi-
ronments, such as the bone marrow and sec-
ondary lymphoid organs, favors disease pro-
gression by promoting malignant B-cell growth
and drug resistance. There is a paradigm shift
in the treatment of selected B-cell malignan-
cies, moving from targeting primarily the ma-
lignant cells toward combining cytotoxic drugs
with agents that interfere with the microen-
vironment’s proactive role. Such approaches
hopefully will help eliminating residual dis-
ease, thereby improving our current therapeu-
tic efforts51-53
.
Future Drug Development
Regarding the Importance of
The study of tumor microenvironment, its
cellular and molecular components, and how
they affect tumor progression, are emerging
topics in cancer research. The factors released
by the tumor cells themselves, in particu-
lar pro/anti-inflammatory molecules or pro/
anti-angiogenic mediators that contribute in
creating an environment, mostly affect or not
the tumor. The events and molecules involved
in this cross talk within the tumor microenvi-
ronment have emerged as attractive targets in
anticancer therapeutic treatments. The stroma
surrounding the cancer cells plays an important
role to study the development, progression and
the behavior of the tumor. It has been report-
ed54
that the interactions between the stroma
and the neoplastic cells are a major factor to
study the cancer growth and its progression.
Tumor microenvironments have contributed
greatly to the study of the tumor development
and progress. The new treatments process for
the tumor cells by tumor microenvironment is
going to offer promising treatment, moreover
helping in the drug discovery and development
for cancer treatment55,56
. The tumors growth
and progression in human is a very complex
topic to understand as their functionality is
multifaceted, for which they rely upon their
growth, invasion and metastasis. The micro-
environment of a tumor is an integral part of
its physiology, structure and functioning, and
it is an essential aspect of the tumor property
as it supplies the required nutrient environment

3862
for the malignant process. A fundamental de-
ranged relationship between tumor and stromal
cells is essential for tumor cell growth, pro-
gression, and development of life threatening
metastasis. The stromal cells within the tumor
microenvironment are genetically stable and
are suitable for therapeutic purposes with min-
imal risk of any side effects or reoccurrence
of the tumor. Improved understanding of this
interaction may provide new and valuable clin-
ical targets for cancer management, as well as
risk assessment and prevention. Non-malignant
cells and secreted proteins from tumor and
stromal cells are active participants in the can-
cer progression.
Conclusions
By monitoring the changes in the tumor mi-
croenvironment using their molecular and cel-
lular profiles, as the tumor progresses, will be
pivotal for identifying cell or protein targets for
the cancer prevention and for their therapeutic
purposes.
Acknowledgements
This work was supported by Zhejiang Provincial Natural
Science Foundation of China (No. LY13H160039 to KFL).
Conflict of Interest
The Authors declare that they have no conflict of interests.
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