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Home , Benign tumor, Tumor microenvironment

European Review for Medical and Pharmacological Sciences 2018; 22: 3855-3864 Tumor microenvironment: recent advances in various treatments

J.-J. WANG1, K.-F. LEI2, F. HAN3

1Department of General , Chun’an First People’s Hospital, (Zhejiang Provincial People’s Hospital Chun’an Branch), Hangzhou, Zhejiang Province, China 2Department of General Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang Province, China 3Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang Province, China

Abstract. – This is a review regarding differ- people per year1. An early detection and treatment ent types of cancer treatments. We aimed at an- of the cancer for a better health management are alyzing the tumor microenvironment and the re- needed. The cancer evaluation is carried out cov- cent trends for the therapeutic applications and ering the nature of cancer, risk assessment, pre- effectiveness for several kinds of . 2 Traditionally the cancer treatment was based vention, and health management . A tumor is an on the neoplastic cells. Methods such as sur- abnormal growth of cells that have no functional gery, radiation, , and immunother- purposes and the potential to spread to the adjoin- apy, which were targeted on the highly prolifer- ing cells or organs or other parts of the body. Not ating mutated tumor cells, have been investigat- all tumors are cancerous; indeed, benign tumors ed. The tumor microenvironment describes the do not spread to other parts of the body3-5. There non-cancerous cells in the tumor and has en- are many types of cancers that affect the humans6 abled to investigate the behavior and response of the cancer cells to a treatment process; it and the cancer cells show no signs or symptoms consists in a that may have a predictive at an early stage of development. The causes of significance for tumor behavior and response the benign tumor are not very clear and they to therapy. These include , immune may be due to reasons such as genetic disorders, cells and cells that comprise the blood vessels. unhealthy food habits, occupational stress, expo- It also includes the proteins produced by all of sure to radiations and/or intake of toxins, may the cells present in the tumor that support the growth of the cancer cells. be caused by infections or , etc.. By monitoring changes in the tumor microen- Generally benign tumors do not require treatment vironment using its molecular and cellular pro- or removal. If there is a recommended treatment, files as the tumor progresses will be vital for the tumor is removed by surgical procedures. The identifying or protein targets for the cancer surgical procedure to remove the tumor should prevention and its therapeutic purposes. not damage the surrounding healthy cells or Key Words: tissues. The non-surgical procedure commonly Cancer, Tumor, Tissue microenvironment, Thera- followed is medication or by a measured quantity peutic applications. 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 Introduction where they are growing. The common types of benign tumors are , fibroids, hemangi- Cancer is one of the major causes of death glob- omas, , , myomas, nevi or ally. More than 11 million people are diagnosed moles, , osteochondromas, , with cancer and this rate has been estimated to etc.7. The common local symptoms of cancer may increase to 16 million by 2020. In 2017, nearly be due to the growth of the mass of the tumor or 13% of all cancers diagnosed in adults ageing 20 its process of ulceration. The growth of the mass and older were rare cancers, defined in this report in the brain may affect the normal functioning of as cancers with fewer than 6 cases per 100,000 the brain, the growth of a mass in the lungs can

Corresponding Author: Fang Han, Ph.D; e-mail: [email protected] 3855 J.-J. Wang, K.-F. Lei, F. Han cause blocks in the bronchus, leading to various Types of Cancer Treatments respiratory disorders. The growth of a mass in With the technological advances the cancer the breast tissues can lead to breast cancer and treatments have undergone tremendous changes the lump can be easily felt. The ulceration of the and the understanding of the underlying biolog- mass leads to bleeding of the tumor and based on ical processes have increased. Various cancer the location shows up various symptoms at vari- treatment methods have been practiced in the past ous stages of the abnormalities. The growth of the and many innovative methods, such as target- masses with the ulcerations may be painless at ed therapy, are being practiced currently. Since times and the individual may feel the pain at the new information and understanding of biological advanced stage of cancer8. The systemic symp- process of cancer tissues are emerging regularly, toms of the tumor occur due to the effects that new treatment procedures and plans are being are unrelated to direct or metastatic spread. The developed and modified to have increased effec- commonly observed symptoms are unexplained tiveness and precision of the treatment, thereby weight loss; fever, feeling fatigue, skin condition enabling the survivability of the patients and im- changes, etc.. The form of cancer proving their quality of life. Cancer can be treat- spreads from its original growth position to the ed by surgery, chemotherapy, ionizing radiation near by locations by spreading to the adjoining therapy, hormonal therapy, targeted therapy etc. cells or tissues, lymphatic spread to regional lymph nodes or by hematogenous spread via the Surgery blood to the various parts of the body9. Treatment of cancer by surgical procedure is commonly practiced for non-hematological can- Treatment for Cancer cers. By surgical method, the surgeon removes There are many types of cancer treatment the cancer tissues from the body. The surgical methods depending on the type of cancer and at procedure can give a complete or partial cure what stage it is advanced. There is no particular for the cancer. There may be side effects of the method or technique foe treatment for cancer. surgical procedure depending on the type of Treatment options can be chemotherapy, surgery, cancer and the health condition of the individual. , hormonal therapy, targeted If the cancer has metastasized to other parts of therapy including immunotherapy, etc.. In some the body, then removal of cancer completely by cases the treatment plan may use a combination surgical process is not possible. The growth of the of the treatment methods to have maximum ef- cancer cells follows the Halstedian model of can- fectives for the treatment. Each of the treatments cer progression10 where the tumors start growing has its own side effects to the patient; then, it is locally and spreading to the lymph nodes and to always necessary for the doctor to discuss the the rest of the body. The treatment of cancer by treatment plans with the patient and their family surgical procedure can be done to cancers that are and obtain their concurrence before proceeding localized and the tumor is of small size. with the treatment plan. In some cases, it is al- Some of the cancer treatments by surgical pro- ways safe for the patient and the doctor to go cedures are mastectomy of breast cancer, brain in for a second opinion for proceeding with any tumor by neurosurgery, prostatectomy for pros- treatment plan. A complete removal of the cancer tate cancer, cancer, lung cancer, tissues without causing damages to the adjoining cancer etc.. Surgically, the aim is to remove the tissues is the required goal for any treatment plan. locally grown tumor or removal of the entire The complete of removal of the cancer tissues is organ if fully spread to the organ. Cancer cells limited by property of the cancer tissues to spread cannot be completely removed by the surgical to the adjoining tissues or spread to distant sites procedure, and even a presence of a single cancer by microscopic metastasis. Treatment procedures cell that is invisible can regrow into a new tumor such as chemotherapy and radiotherapy have neg- and spread to other parts of the body. The chanc- ative side effects on the normal healthy tissues. es of reoccurrence of the cancer can be assessed The basic purpose of a cancer treatment plan is by carrying out by the pathologist; the to have cure for the cancer and, when a complete surgically removed tissues is analyzed for the cure is not possible, the treatment plan should be presence of healthy tissues. Evaluating the pres- to suppress the cancer to a subclinical state and ence of healthy or cancerous tissues, the amount maintaining the normal state for the subject to of cancerous tissues left in the patient can be an- lead a normal quality of life. alyzed, which is useful to investigate the staging

3856 Tumor microenvironment: recent advances in various cancer treatments of cancer11,12. Other treatment procedures, such as stages or if the tumor is located at highly vulner- chemotherapy, can be done before or after that the able locations. The cancer cells grow and divide surgical procedure is carried out to remove the faster than the normal cells. The radiation therapy affected tissues. uses a specialized equipment to deliver measured doses of radiation to the cancer cells. The radia- Chemotherapy tion therapy kills tumor cells by damaging their The method of chemotherapy is carried out DNA either directly or by creating free radicals through the use of drugs, usually known as within the cells that can in turn damage the DNA. anticancer drugs, to kill or destroy the cancer This treatment uses high-energy ionizing radi- cells. These drugs interfere with the growth of ation such as x-rays. These treatments are com- tumors and even destroy the cancer cells. The monly practiced only on adults and in children chemotherapy is generally considered as an ef- they have significant side effects. fective method of treatment of cancer; however it can cause severe side effects as they can destroy Immunotherapy either healthy cells or tissues. The side effects Immunotherapy is a method of cancer treat- caused by the chemotherapy treatment depend ment that helps the to fight upon the type of drugs being used for treatment cancer. This is also known as biologic therapy, and the type of the cancer, its locations and also which stimulates the disease fighting mechanism on the individual’s response to the particular within the patient’s body to fight the cancer. A chemotherapy treatment. The side effect on the high number of researches have been carried out cancer patient is not related to the effectiveness of to treat the cancer by immunotherapy, such as the treatment and it vanishes once the treatment monoclonal antibodies that block specific protein process is completed. Generally the chemothera- function by binding to cancer cells, which train py treatments are prescribed to a subject in mea- the immune system to recognize and attack the sured quantity or in a specific number of intervals cancer cells. This method of treatment is safe and over a period of time. Sometimes the chemother- does not have any major side effects. apy is administered as two or more drugs at the same time; this method of treatment is known as Therapy combination chemotherapy13. The hormone therapy fights cancer by chang- ing the amount of in the body to treat Radiation Therapy certain types of cancer that depend on these Radiation therapy method of cancer treatments chemicals to grow and spread. This treatment makes use of high doses of radiation generally method is used for treating cancers of breast, re- ionizing radiation to kill cancer cells and destroy productive system and prostrate. The side effects the tumor tissues. This treatment is commonly depend on the type of cancer, age, sex and the used in conjunction with the surgery to remove or type of drug used in the treatment. reduce the size of the tumors. The radiation thera- py is commonly delivered externally or internally Targeted Therapy to the desired location. The radiation therapy giv- The targeted treatment of cancer targets the en both internally or externally can also damage cancel cells that re-enable the cells to grow, the normal cells and induce the side effects of the divide and spread. Targeted treatment uses spe- normal cells due to these ionizing radiations14. cific agents for the deregulated proteins of cancer The radiation therapy is commonly used to cells. The small molecule targeted therapy drugs treat most of the types of tumor such as cancers are generally inhibitors of enzymatic domains on of the brain, breast, cervix, larynx, liver, lung, the mutated, overexpressed, or otherwise critical pancreas, prostate, skin, , uterus, etc.. proteins within the cancer cells. Radiation therapy is also used to treat cancers like and lymphoma15. The radiation Tumor Microenvironment dose to be delivered to the cancer or tumor site Tumor Microenvironment (TME) is the cel- depends upon various factors such as age of the lular environment in which the tumor exists in person, type of the tumor, location of the tumor, the human system. It includes the blood vessels, and possible side effects on the radiation source , cells that contribute to the immunity, on the nearby tissues and organs. The radiation marrow-derived inflammatory cells, lym- therapy is not used if the cancer is at the advanced phocytes, signaling and the

3857 J.-J. Wang, K.-F. Lei, F. Han

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

Figure 1. Tumor microenvironment shows the cell-cell interactions, which contribute to cancer cell progression, invasion, and metastasis.

3858 Tumor microenvironment: recent advances in various cancer treatments and various other components of the tumor that Recent Advances in are supportive to the tumor microenvironment. Tumor Microenvironment Most of the cancers are or cancers The conventional cancer therapy treatments commonly grow in the epithelial tissues that are are effective to the cancer cells but they are also not vascularized23. The vascular structures of cause of damage to the healthy tissues and cells. the tumors are leaky and they accumulate mol- New treatment methods of cancer treatments are ecules in the blood stream to a greater extent as being practiced for the treatment of cancer and compared to that of the normal tissues. These its molecular mechanisms are well characterized. have enhanced permeability and retention ef- The slow or rapid growth of the tumors cells fect, and the vasculature of the tumor is gener- results in the inability of the blood vessels to ally leaky, accumulating the molecules in the provide oxygenation and nutrients to the tumor blood stream instead of the normal tissues. The cells, leading to oxygen deficient or hypoxic re- tumor microenvironment is generally hypox- gions within the tumor. Tumor microenvironment ic; since the tumor mass increases and grows will enable to investigate the clinical trials tests, further away from the blood vessels leading to many types of treatment such as new drugs, new genetic disability, the lack of oxygen can also approaches to treatment method using surgery cause glycolytic behavior in cells, inducing the or a radiation therapy or a new combination of greater cell migration in-vivo and in-vitro. This treatments. may also lead to degradation of the extra cellu- Tumor microenvironment is considered im- lar matrix (ECM)24,25. The reactive stroma cells portant for the cancer therapy due to the varying of a are the connective tissues locat- levels of the influence of the different treatments ed below the basal lamina, such as fibroblasts, methods used. The various drawbacks of the ECM, cells that are responsible for immunity conventional methods of tumor treatments are and other molecules and cells. The stroma sur- that the tumor vascular structures are leaky and rounding the tumor often reacts to the intrusion highly disoriented; they lack of oxygenation to through the , similar to the ways the tumor core, making it immune to radiation they respond to wounds26. The inflammation treatments, since to be delivered, the cells far can enhance the angiogenesis and drastically from blood vessels required – and not receive – increase the cell cycle and prevent cell death the necessary nutrients or any chemotherapy sub- and augment tumor growth27. Carcinoma asso- stances. Due to these drawbacks, tumor micro- ciated fibroblasts (CAFs) are a heterogeneous environment and an effective therapeutic method group of fibroblasts whose functionality is tak- for cancer prognosis and treatment are needed. en away by the cancer cells and is redirected to- Current researches on tumor treatments are fo- wards carcinogenesis28. CAFs are derived from cusing on microenvironment as the treatment ef- normal fibroblasts in the surrounding stroma, ficiency of the anticancer therapies differs signifi- but can also come from , fibrocytes, cantly in comparison of those found in the normal mesenchymal cells, cells, epi- tissues. Then, investigations are now focusing on thelial mesenchymal transition (EMT) or en- the tumor microenvironment as a separate can- dothelial mesenchymal transition (EndMT)29-31. cer associated entity that may be targeted. New CAFs in vitro do not retard the cancer growth methodologies are identified and are effective and perform several functions that support the through specific targeting of the tumor micro- tumor growth32. CAFs also secrete a vascular environment. The tumor microenvironments are endothelial growth factor (VEGF), fibroblast extensively exploited in the tumor vasculature, growth factor (FGFs), platelet derived growth as the oxygen deprives cancer cells, which are factor (PGGF) and other pro-angiogenic sig- effective to the radiation therapy. nals that will induce the angiogenesis33. CAFs The patients develop resistance to also secrete a transforming growth factor beta both chemotherapy and targeted-therapy drugs. (TGF-β) that is associated with EMT and – by The chemotherapy and targeted therapies, im- this process – the cancer cells metastasize and mune checkpoint blockade treatment methods inhibit the cytotoxic T cells and natural killer commonly practiced, are not effective to all the T cells34,35. CAFs restrict the cell distribution melanoma patients. A number of contributing by physically excluding them as medicated by factors such as gene mutations, the physiology their cellular matrix and also excluding them of the cell functionality and tumor heterogeneity, via biosynthesis of CXXL12. contribute to the resistance of the tumor cells

3859 J.-J. Wang, K.-F. Lei, F. Han to the treatment provided. Recent investigations the pathogenesis of most B Cell , and carried out have shown the role of inflammatory their potential therapeutic opportunities for tar- tumor microenvironment. Furthermore, it has geting oncogenic pathways, is possible now and been proven that the multi-modal approach for in the future41. targeting the microenvironment, in addition to Studies were carried out to analyze the tem- malignant cells, is necessary for a better therapy poral changes in gene expression when breast response36. cancer cells survive and grow on brain, bone Angiogenesis is a formation of new blood ves- marrow, and lung tissue maintained in an in vivo sels involving the migration, growth and differen- culture system, as models of the metastatic colo- tiation of endothelial cells that line the inside wall nization of these tissues. It was observed that the of the blood vessels, which are controlled by the transient activation of the genes associated with chemical signals in the body. Controlling the an- homeostasis and stress, later by the elaboration of giogenesis is a critical step in the cancer progres- cell morphology and cell division, lead the cells sion and its potential therapy. The role of tumor adapted to thrive in the host tissue microenviron- microenvironment in the control of angiogenesis ment42. and the method of dissection of the molecular in- Breast cancer treatment using the microen- teractions enhances the prognostic and facilitates vironment by targeting the generation of DNA the targeted therapy37. intercalation inhibits topoisomerase II and inter- Understanding of the tumor stroma in ad- feres with the DNA replication. The chemother- vancing cancer is improved by the scaffolding apeutic agents kill cancer cells and the treatment and matrix-based 3D systems. The drug delivery triggers a stromal reaction leading to TNF-α systems made from synthetic and natural bioma- production by endothelial and other stromal cells. terials deliver drugs to kill stromal cells or repro- The network of the endothelial-carcinoma my- gram the microenvironment for tumor inhibition. eloid signaling interactions provides a mecha- 3D models have been used to understand the nism linking chemo-resistance and metastasis tumorigenesis. Also, the effects of tumor stroma with possibility for intervention43. for cancer treatment for different drug delivery Development of the prostrate cancer is not on- systems were analyzed38. ly confined to the cancer epithelial cell, but also Chemoprevention is the use of pharmacologic involves the tumor microenvironment. Prostate or natural agents that inhibit the development of cancers metastasize to the skeleton, and there is invasive cancer either by blocking the DNA dam- considerable research being carried out to ana- age that initiates or by arresting or lyze the interaction between prostate cancer epi- reversing the progression of premalignant cells, thelial cells and the bone microenvironment. The in which such damage has already occurred. signaling pathways do exist between epithelial Studies39 of primary dysfunction in the tumor cells, stromal cells and the extracellular matrix to microenvironment and the epithelial dysfunction support tumor progression from the primary site are critical for the carcinogenesis, especially for to regional lymph nodes and the distant metasta- the cancer chemoprevention. ses. The prostate cancers metastasize to the skel- Hypoxia tumor cells are resistant to the cancer eton and research is being carried out to study the therapies and the reasons may be due to the ad- interactions between prostrate cancer epithelial vanced stages of . These cells inhibit cells and the bone microenvironment. The signal- tumor cell differentiation and play a direct role in ing pathways that are involved in normal prostate the maintenance of the cancer stem cells. They and bone development lead to dysregulation in were found to have profound impact on the evo- cancer, thereby simulating excessive lution of the tumor stromal microenvironment. and neovascularization and leading to invasive The hypoxia may enable to create a microenvi- properties to the epithelial cells, weakening of ronment to differentiate the tumor cells and the the antitumor immunity and castrate-resistant stromal cells, suggesting that targeting hypoxic disease. This study regarding the relationship stem cells may be a key to successful tumor between cancer epithelial cells and the organ spe- management40. cific microenvironment enables the development Tumor cells retain a range of dependence on of novel therapeutic techniques44. interactions with the non-malignant cells and the Acquired resistance to anticancer treatments stromal elements that constitute the tumor micro- is an essential barrier to reduce the morbidity environment. By understanding the interactions, and mortality of the malignant tumors. Tissue

3860 Tumor microenvironment: recent advances in various cancer treatments microenvironments have been found to influence Though there are many therapeutic advances cellular phonotypes and to have susceptibility to for the cancer treatments, most of the mature toxic insults. The expression of WNT16B in the B-cell remain incurable. Evi- prostate tumor microenvironment attenuated the dence suggests that crosstalk with accessory effects of cytotoxic chemotherapy in vivo, there- stromal cells in specialized tissue microenvi- by promoting tumor cell survival and disease ronments, such as the bone marrow and sec- progression. These results delineate a mechanism ondary lymphoid organs, favors disease pro- by which genotoxic therapies given in a cyclical gression by promoting malignant B-cell growth manner can enhance subsequent treatment resis- and drug resistance. There is a paradigm shift tance through cell nonautonomous effects that in the treatment of selected B-cell malignan- are contributed by the tumor microenvironment45. cies, moving from targeting primarily the ma- The bone marrow microenvironment enables lignant cells toward combining cytotoxic drugs the survival, differentiation, and proliferation of with agents that interfere with the microen- hematopoietic cells, which are supported by fibro- vironment’s proactive role. Such approaches blast-like bone marrow stromal cells, osteoblasts, hopefully will help eliminating residual dis- and osteoclasts, that secrete soluble factors and ex- ease, thereby improving our current therapeu- tracellular matrix proteins that mediate these func- tic efforts51-53. tions. This makes the normal hematopoietic cells and epithelial tumor cells that metastasize to bone, Future Drug Development protect from the chemotherapeutic agents. Due Regarding the Importance of to this drug resistance, tumor cells are protected Tumor Microenvironment from induced by both chemotherapy and The study of tumor microenvironment, its physiologic mediators of cell death, thereby allow- cellular and molecular components, and how ing them to survive and lead to minimal residual they affect tumor progression, are emerging disease, increasing the probability for development topics in . The factors released of acquired drug resistance46-48. by the tumor cells themselves, in particu- is one of the major caus- lar pro/anti-inflammatory molecules or pro/ es of cancer death in the world. The structural anti-angiogenic mediators that contribute in proteins in the microenvironment of pancreatic creating an environment, mostly affect or not cancer can be modified or targeted, including the the tumor. The events and molecules involved hyaluronan, and secreted protein, acidic in this cross talk within the tumor microenvi- and rich in cysteine. Current methods are being ronment have emerged as attractive targets in exploiting rather than targeting/destroying the anticancer therapeutic treatments. The stroma microenvironment by normalizing the structur- surrounding the cancer cells plays an important al proteins, reversing epithelial-to-mesenchymal role to study the development, progression and transition. The results have shown beneficial re- the behavior of the tumor. It has been report- sults that can be clinically evaluated49,50. ed54 that the interactions between the stroma There are three methods commonly used to de- and the neoplastic cells are a major factor to tect the lung cancers: (1) measurement of partial study the cancer growth and its progression. oxygen pressure (pO2) with needle electrodes; (2) Tumor microenvironments have contributed detection of hypoxia-induced proteins in tumor greatly to the study of the tumor development or blood; (3) imaging hypoxia and tumor vascu- and progress. The new treatments process for lature49. Presently, there are several promising the tumor cells by tumor microenvironment is modalities to image hypoxia and the tumor vas- going to offer promising treatment, moreover culature; these include dynamic perfusion imag- helping in the drug discovery and development ing and positron emission tomography scanning for cancer treatment55,56. The tumors growth with radiolabeled nitroimidazoles. To evaluate and progression in human is a very complex the effects of these agents, a non-invasive mean topic to understand as their functionality is of imaging the TME is critical. To date, there are multifaceted, for which they rely upon their several promising modalities to image hypoxia growth, invasion and metastasis. The micro- and the tumor vasculature; these include dy- environment of a tumor is an integral part of namic perfusion imaging and positron emission its physiology, structure and functioning, and tomography (PET) scanning with radiolabeled it is an essential aspect of the tumor property nitroimidazoles. as it supplies the required nutrient environment

3861 J.-J. Wang, K.-F. Lei, F. Han for the malignant process. A fundamental de- 6) Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, ranged relationship between tumor and stromal Winer R, Clifford GM. Human papillomavirus type cells is essential for tumor cell growth, pro- distribution in invasive and high- grade cervical : a meta-analysis update. gression, and development of life threatening Int J Cancer 2007; 121: 621-632. metastasis. The stromal cells within the tumor 7) Langloss JM, Enzinger FM. Value of S-100 protein microenvironment are genetically stable and in the diagnosis of soft tissue tumors with partic- are suitable for therapeutic purposes with min- ular reference to benign and malignant Schwann imal risk of any side effects or reoccurrence cell tumors. Lab Invest 1983; 49: 299-308. of the tumor. Improved understanding of this 8) Walter FM, Rubin G, Bankhead C, Morris HC, Hall interaction may provide new and valuable clin- N, Mills K, Dobson C, Rintoul RC, Hamilton W, Em- ical targets for cancer management, as well as ery J. Symptoms and other factors associated with time to diagnosis and stage of lung cancer: a risk assessment and prevention. Non-malignant prospective cohort study. Br J Cancer 2015; 112: cells and secreted proteins from tumor and S6-S13. stromal cells are active participants in the can- 9) Wong SY, Hynes RO. Lymphatic or hematogenous cer progression. dissemination: how does a metastatic tumor cell decide? Cell Cycle 2006; 5: 812-817. 10) Subotic S, Weiss H, Wyler S, Rentsch CA, Rassweiler Conclusions J, Bachmann A, Teber D. Surgical treatment of lo- calised renal cancer. World J Urol 2013; 31: 689- By monitoring the changes in the tumor mi- 695. croenvironment using their molecular and cel- 11) Mieog JS, van der Hage JA, van de Velde CJ. Neoad- lular profiles, as the tumor progresses, will be juvant chemotherapy for operable breast cancer. Br J Surg 2007; 94: 1189-1200. pivotal for identifying cell or protein targets for 12) Jafri, SH, Mills, G. Neoadjuvant chemotherapy in the and for their therapeutic lung cancer. Therapy 2011; 8: 23-31. purposes. 13) Takimoto C, Calvo E. Principles of Oncologic Phar- macotherapy (2008). Ch 3 Appendix 3, in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Acknowledgements Approach, 11th edition. Available: http://www.can- This work was supported by Zhejiang Provincial Natural cernetwork.com/cancermanagement-11/. Science Foundation of China (No. LY13H160039 to KFL). 14) D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A. Biochemical out- come after radical prostatectomy, external beam Conflict of Interest radiation therapy, or interstitial radiation thera- The Authors declare that they have no conflict of interests. py for clinically localized prostate cancer. JAMA 1998; 280: 969-974. 15) Evans AE. Central nervous system involvement References in children with leukemia. Cancer 1964; 17: 256- 258. 1) Siegel RL, Miller KD, Jemal A. Cancer Statistics, 16) Joyce JA, Fearon DT. exclusion, immune priv- 2017. CA Cancer J Clin 2017; 67: 7-30. ilege, and the tumor microenvironment. Science 2) Anand P, Kunnumakkara AB, Kunnumakara AB, Sund- 2015; 348: 74-80. aram C, Harikumar KB, Tharakan ST, Lai OS, Sung 17) Spill F, Reynolds DS, Kamm RD, Zaman MH. Impact B, Aggarwal BB. Cancer is a preventable disease of the physical microenvironment on tumor pro- that requires major lifestyle changes. Pharm Res gression and metastasis. Curr Opin Biotechnol 2008; 25: 2097-2116. 2016; 40: 41-48. 3) Folkman J. Tumor angiogenesis: therapeutic 18) Korneev KV, Atretkhany KN, Drutskaya MS, Griven- implications. N Engl J Med 1971; 285: 1182- nikov SI, Kuprash DV, Nedospasov SA. TLR-signaling 1186. and proinflammatory cytokines as drivers of tum- 4) Anna Kane Laird. Dynamics of tumour growth: origenesis. Cytokine 2017; 89: 127-135. comparison of growth rates and extrapolation of 19) Hanahan D, Coussens LM. Accessories to the growth curve to one cell. Br J Cancer 1965; 19: crime: functions of cells recruited to the tumor mi- 278-291. croenvironment. Cancer Cell 2012; 21: 309-322. 5) Merlo LM, Pepper JW, Reid BJ, Maley CC. Cancer as 20) Anastasiou D. Tumour microenvironment factors an evolutionary and ecological process. Nat Rev shaping the cancer metabolism landscape. Br J Canc 2006; 6: 924-935. Cancer 2017; 116: 277-286.

3862 Tumor microenvironment: recent advances in various cancer treatments

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