Sunlightâ€”Can It Prevent as well as Cause Cancer?1 · SUNLIGHT: PREVENTION OF CANCER Fig. 2....

ICANÅ’RRKSKARCH55.41114-40:2.Septemberis, i<ws|

Perspectives in Cancer Research

Sunlightâ€”Can It Prevent as well as Cause Cancer?1

George P. Studzinski2 and Dorothy C. Moore

Dt'lHirtnu-nl oj Ijihartiton' Medicine ÃintlPiillÃ¬itÃ¬ti\>\.VMD-New Jct'*c\' Mt'ilictil School. Newark, New Jersev 07ÃŒ03

Abstract

Kxccssive exposure tu sunlight is known to damage the skin. However,the emphasis of most studies has heen on the consequences of sunlightexposure to fair-skinned individuals, and the situation of people with

heavy skin pigmentation residing in, or migrating to, geographic locationswith limited sunlight incidence has been largely neglected. Recent epidemiolÃ³gica! studies suggested the hypothesis that sunlight deprivation, andthe associated reduction in the circulating levels of vitamin I), (vit l),iderivatives may lead to the increased incidence of the carcinomas of thehreast, colon, and prostate. Two endocrine pathways may mediate theseeffects. The pineal function can potentially he involved, hut the formationof vit I), derivatives is gaining credibility as a mechanism for the retardation of cancer progression. Kvidence is accumulating that such compounds, c..!;.. 1,25-dihydroxyvitamin II, (1.25I),) induce differentiation of

several neoplastic cell types, arrest or retard their proliferation, and act aschemoprcventivc agents in animal carcinogenesis. We also propose thatthe antineoplastic effects of vil I), derivatives are exerted at several stepsin tumor progression and that immunomodulating effects of I.-51), maycontribute to these effects of sunlight. The recent findings that commoncancers, e.g., carcinoma of the prostate and the breast, behave moreaggressively in black Americans than in white Americans may be explained on this basis. Although more data are needed on the effects ofsunlight on the circulating levels of 1.25D,, a corollary of this hypothesisis that there should be no broad condemnation of moderate sunlight exposure, as it may be available in insufficient amounts to someAmericans.

Introduction

It has heen apparent for a long time that the skin of individualsexposed to strong sunlight becomes damaged. The damage is manifested as accelerated changes associated with aging and frequentlyleads to the development of various forms of skin cancer (1). This isparticularly obvious when the affected individuals have lightly pig-

mcnlcd skin and migrate to areas nearer the equator, such as people ofCeltic descent living in Australia (2) or Europeans moving to Israel(3). However, the obverse of this situation, e.g., when people withheavily pigmented skin move from Africa to the Northern latitudes ofthe American continent and are exposed to a greatly decreased intensity of sunlight, has rarely been considered. Therefore, it is importantto evaluate the hypothesis that reduction of sunlight exposure maycontribute to the increased incidence of the common cancers inAmericans with varying degrees of skin pigmentation and to determine the possible mechanisms of such effects of sunlight.

It is not surprising that those confronted with the horrendousdamage inflicted by the sun on the skin of fair-complexioned indi

viduals are reluctant to accept the possibility that exposure to sunlightcan also have beneficial effects, if the exposure is moderate (4). Yet,a number of considerations point to this conclusion. The Darwinian

Received 4/20/45; accepted 7/l<W5.The costs of publication of this article were defrayed in part In the payment of page

charges. This article must therefore he hereby marked iiilverliseniÃ¯ni in accordance withIS U.S.C. Section 1734 solely to indicate Ihis laci.

1Supported by USPHS Granls ROI-CA44722 and R2y-DK45270.-"To whom requests for reprints should be addressed, at Department of Laboratory

Medicine and Pathology. UMD-New Jersey Medical School. 185 South Orange Avenue.Newark. NJ 07103.

view of evolution suggests that loss of body hair in Homo sishould have some survival advantage, and it is difficult to think ofreasons other than that this provides ready access of sunlight to theskin. Secondly, it has been known since 1840 that sunlight deprivationdue to air pollution or the proximity of tall buildings in cities ofindustrialized countries results in bony deformities of rickets andosteomalacia, which can be corrected by sunlight (5). Later, in theearly years of this century, the same corrective effect was obtained bynutritional supplementation with vit D3 (6). It seems presumptuous to

believe that all benefits of sunlight were discovered over 70 years agoand are limited to the prevention of rickets, osteomalacia, or osteoporosis. Indeed, recent epidemiolÃ³gica! studies suggest the hypothesisthat sunlight deprivation can be. in part, responsible for the increasingincidence of some of the most common malignancies afflicting populations of temperate climates: carcinomas of the breast, colon, andprostate (7-12). Additional support for the view that the physiological

metabolites of vit D generated as the result of skin exposure tosunlight, or to a variable extent provided by the diet, can reduce theincidence of these carcinomas is provided by experiments with laboratory animals and human cells in culture (13-23). In this article, we

summarize the evidence that the following two propositions derivingfrom the above hypothesis should be seriously considered: (</) moderate exposure to sunlight can retard some forms of neoplastic progression in most individuals, and (/>) lack of sufficient sunlightcontributes to the known high incidence of carcinoma of the prostatein black American men and to the more aggressive progression ofcarcinoma of the breast in black women. We also summarize themechanisms through which sunlight-generated vit D metabolites may

inhibit neoplastic progression.

Effects of Sunlight on Internal Organs

There are three known ways in which sunlight may influencefunctions and proliferation of cells in internal organs. One is theinhibition of pineal hormone production following perception of intense visible light by the eyes (24), and perhaps also by diffusionthrough the skull, and another by dissemination throughout the bodyof 1.25D, following the initiation of its biosynthesis in UV-irradiated

skin. In addition, intense UVB light in mice enhances growth ofmelanoma by presumably immunological mechanisms (25), and UVAsuppresses cellular immunity in people and thus increases tumoroutgrowth (26, 27). These effects are believed to be mediated bysystemic T-lymphocyte-mediated immunosuppression (28), possiblydue to the release of epidermal cytokines triggered by UV-induced

DNA damage. The topic of photoimmunology has recently been fullyreviewed by Kripke (28).

Effects of Sunlight on Endocrine Function of the Pineal (.land.The physiological function of the pineal gland in humans is not fullyknown. However, phylogenetic considerations indicate that the pinealsecretes a hormone, melatonin, which inhibits reproductive functions,and in invertebrates causes lightening of skin color by inducing

"The abbreviations used are: vil D, vitamin D: vil Dâ€žvitamin D,; 1.25D,, 1.25-

clihydnixy vitamin I),: 7-DHC. 7-dehydrocholcslerol; 25Dâ€ž25-hydroxyvilamin D,: VDR.vitamin D receptor.

4(114

Research. on October 9, 2020. © 1995 American Association for Cancercancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

SUNLIGHT: PREVENTION OF CANCER

retraction of dendritic cell processes containing melanin (Ref. 29;Fig. 1). Secretion of melatonin is inhibited by sunlight; in lowervertebrates, such as some lizards, the pineal is the "dorsal eye" being

directly accessible to light, and as a component of the endocrinesystem, regulates the animal's seasonal changes in reproduction and

level of activity. For instance, the low level of sunlight in the winterallows secretion of melatonin, which inhibits reproductive and physical activity and may lead to hibernation. Increasing intensity ofsunlight in the spring inhibits melatonin secretion, and this has widespread effects on the animal's activity, and increases skin pigmentation.

In human, sunlight is sensed by the "lateral" eyes and the nonvisual

pathway (i.e.. inferior accessory optic tract) and is transmitted throughneuronal connections in the brain to the pineal. There is no known linkbetween pineal function and human cancer, but in view of the extremecomplexity of endocrine regulation of the growth of cells comprisingthe reproductive systems, the possibility of such a link cannot beexcluded. Hormone-responsive cancers, such as carcinoma of the

breast and prostate, are potential candidates for such regulation.Further, since melatonin reduces the area of the skin protected fromsunlight by melanin, inadequate function of the pineal gland maycontribute to sunlight-induced skin cancers, but this is uncertain, since

its effects on melanin distribution has only been demonstrated inlower animals.

Effects of Sunlight on the Endocrine Eunctions of the Skin. Incontrast to the pineal gland, which responds to the visible light

components of sunlight, the skin acts as the receptor for the sun's

UVB rays, a subject comprehensively covered by Webb and Holick(30). These rays (280-320-nm portion of the electromagnetic spectrum) initiate the signal by conversion of 7-DHC (provitamin D,) topre-vitamin D,, which under the influence of heat, also provided by

sunlight or by normal body temperature, undergoes isomerization tovit D, (30). This molecule is carried by the blood stream to the liver,where hydroxylation in the 25 position of the steroid ring produces theprincipal plasma form of vit D, 25DV Further hydroxylation, principally in the kidney, produces the physiologically active form 1,25D,or its alternate metabolite such as 24,25-dihydroxyvitamin D,. The

active form, 1.25D,, is a full member of the endocrine system, and assuch interacts with virtually every organ in the body (31, 32). Especially noteworthy is its interaction with the sex and pituitary hormones(32-34), e.f>.,the promotion of la-hydroxylation of 25D, by prolactin

(34), since some of these interactions provide a mechanism for participation of 1.25D, in the control of cell growth in the reproductiveorgans. A simplified representation of the generation of the activeform of vit D in the skin, liver, and kidney is presented in Fig. 2.

Production of vit D, by photoconversion of 7-DHC' depends on a

number of factors in addition to the intensity of sunlight. Although7-DHC is present in all layers of the skin, its concentration is highest

in stratum spinosum and stratum basale (30). Therefore, localizationof 7-DHC in relation to the distribution and to the amount of melanin

is also an important factor for its conversion to previtamin D,.

Fig. 1. Impaci of sunlight on the pineal gland.Visible rays from the sun are sensed by the eye andtransmitted to the pineal gland. It has also beensuggested that light is sensed by the pineal gland bydiffusing dirteal gland ismelatonin isductive funettrophins. Incirculating min the skin, although this has noi been demonstratedin humans.

tly through the skull. When the pin-timulated by light, the secretion ofeduced, resulting in increased repro-)ii mediated by the pituitary gonado-'wer vertebrates, reduced levels oflatonin produces melanin expansion

Reproductive^Function |

Skin

41115




Fig. 2. Generation of the active form of vitamin D. Theskin acts as a receptor for the sunlight's UVB rays. The

UVB rays convert 7-DHC to previtamin D, which thenundergoes a heat-induced (wavy lines) isomerization in

the skin to vit Dv Vit D3 is carried in the bloodstream tothe liver, where it is hydroxylated to 25D3, and then to thekidney, where it is further hydroxylated to its physiologically active form 1,25D,. The left side of the figurerepresents the skin of a heavily pigmented individual, inwhich melanin is abundant. The melanin also absorbsUVB light and, therefore, competes with 7-DHC for the

UVB light radiation, resulting in low levels of previtaminD, unless the exposure is prolonged or of a higher intensity. The rÃ.c/iÃside of the figure represents the skin of alightly pigmented individual through which the UVB rayshave less competition for the UVB light radiation. Thisresults in higher levels of previtamin D, but excessiveirradiation by the UVB rays leads to a further photoconversion of previtamin D to lumisterol or tachysterol. Theseare inactive and do not serve as precursors of vit Dv Thefigure is a schematic representation not meant to accurately portray the exact anatomical features. This figurehas been modified from Fig. 2 in Ref. 30.

C/5

Kidney

Furthermore, intense or continuous UV irradiation of previtamin D,converts it to the biologically inactive lumisterol and tachysterol,rather than to vit D3 (30). Thus, the duration of the exposure and theintensity of the components of sunlight reaching basal levels of theepidermis determine whether the photoconversion of 7-DHC is es

sentially destructive or results in the production of vit D3. Clearly,therefore, melanin, which prevents UV light from reaching the deeperlayers of the epidermis, and possibly melatonin, which regulates thedistribution of melanin in the epidermis, are important for the outcomeof the interaction of sunlight with the skin.

Another method through which one could improve the vit D statusof an individual is by supplementation in the diet. However, this isdifficult to achieve adequately, and the relative importance of diet andsunlight to vit D status varies with age and geographical location (Ref.35 and references therein). An evaluation of the relative contributionsof diet and sunlight exposure to the circulating levels of 25D3, aconvenient marker of vit D status, showed that diet failed to providea sufficient amount of vit D for elderly individuals who had minimalsun exposure (36). One of the primary reasons for these results is that

the amount of vit D present in the diet is variable (37, 38). The naturalsources of vit D include fish liver and milk. In addition, milk ormargarine in the United States and some European countries aresupplemented with synthetic forms of vit D, but this attempt atfortification has not been reliable in terms of the amount of vit Dconsumed (39). The intake of milk and margarine are also highlyvariable, the extreme case being total avoidance of milk by those withlactose intolerance, and consumption of fish liver is low in thiscountry. Thus, many Americans must rely either on supplementationwith vit D preparations or on the sun's rays reaching the basal levels

of the epidermis for their supply of vit Dv

Molecular Mechanisms of Endocrine Actions of 1,251),

It is now well known that in addition to its participation in theregulation of calcium homeostasis, 1,250, is a steroid hormone whichinteracts with many cell types. The endocrine effects of 1,25D3 aremediated by a nuclear protein, the VDR. When combined with1,25D3, the VDR acts as a transcription factor that modulates the

4016



SUNLIGHT: PRKVENTION OF CANCER

ChronicIrritation

Chemicals

GeneticDefects-*,

Fig. 3. The possible fules of a proliferating eell that affecttumor formation and progression. Step #/. initiation of carci-

nogencsis; step #2, tumor progression; slop #3, induction ofdifferentiation: step #4. induction of apoptosis; step #5, tumor cell invasion and spread.

Progressionof geneticchanges

Apoptotic cell

Neoplastic phenotype but "in situ"

Invasive properties

Infiltrating and Metastatic cancer cells

activity of a number of human genes (40, 41). Interestingly, it hasbeen shown recently that VDR interacts with a retinoid X receptor(RXRa), thus indicating that signals provided by vit D and by vitaminA can converge in the cell nucleus (42). Derivatives of both thesevitamins have anticancer activity (summarized in Refs. 41, 43, and44), so that the interaction of these receptors may have significancefor the control of cellular growth.

Genes whose activity is modulated by 1,25D, include those thatencode proteins that provide specialized cellular functions, e.g.,osteocalcin (45), and those that encode proto-oncogenes, e.g.,c-fos, c-jun, and c-mvc (46 â€”48). The down-modulation of c-mycby 1,25D, may be important for the proposed cancer chemopre-ventive effects of 1,25Dâ€žsince this proliferation-related gene (49)is frequently amplified and over-expressed in several human tumor

types, including carcinoma of the breast (50). Overall, it has beenestimated that the activity of at least sixty nuclear genes isregulated by I,25D, (51).

Effects of Sunlight and Vit I>, Derivatives on the Fate ofNeoplastic Cells

The concept of neoplastic progression implies that tumor cellsacquire new properties as the tumor enlarges (52). The molecular

basis for this progression, driven by the genetic instability of neoplastic cells (53), is provided by activation of proto-oncogenes (54) and

loss or Â¡nactivation of tumor suppressor genes (55). A condensedscheme of neoplastic progression, including the stages that are de-

monstrably influenced by sunlight, directly or mediated by vit D,derivatives, is shown in Fig. 3. It includes:

Initiation of Carcinogenesis by Sunlight

There is abundant evidence that excessive sunlight exposure is animportant cause of several forms of skin carcinoma (1). For instance,the incidence of squamous cell carcinoma and basal cell carcinoma iswell documented to be proportional to the cumulative life-time sun

light exposure, and these carcinomas typically occur on areas of thebody exposed to sunlight (1). However, there is still a controversy asto the extent that the rising incidence of melanoma can be attributedto increased exposure to sunlight, since some observations suggestpreventive effects of suntanning on the development of this malignancy (4). 1,25D3 serum levels were found to be slightly lower inpatients with melanoma than in the control group, but the differencewas not statistically significant in this limited study (56). However,growth of human melanoma cells in culture or implanted into mice

4017



SUNLIGHT:PREVENTION OF CANCER

has been shown to he inhibited by 1,25D, (57, 58). Thus, except forlentigo maligna melanoma, which is common on the hands and theface (59), neither carcinogenic nor preventive effects of sunlight onhuman melanoma can be claimed with certainty. However, it isestablished that immunosuppression contributes to the UV-induced

skin cancer in experimental animals.

Effects of 1,25D, on Tumor Progression

Studies of Human Cells in Culture. Numerous reports demonstrate that 1,25D3 can retard or arrest proliferation of human cancercells in culture (Table 1). These include cells cultured from carcinomaof the colon (60, 63, 67), breast (13, 68, 69), prostate (17, 18), severalforms of leukemia (20, 46, 83), and from other neoplasms, such asgynecological cancers (90).

Studies in Experimental Animals. Equally well documented arethe protective effects of 1,25D3, and of its less hypercalcÃ©mieanalogues, on carcinogen-induced tumor formation in experimental ani

mals (Table 2). For instance, topical applications of 1,25D3 inhibit thephorbol ester promotion of dimethylbenzanthracene-initiated mouse

skin carcinogenesis (100, 101), whereas systemic administration of1,250;, inhibits experimental colon carcinogenesis in rats (22, 95). Inthis system, however, interpretation is complicated by another variable, i.e., the dietary calcium levels, since there are data suggestingthat dietary calcium may inhibit the development of colon cancer (93,94, 105). Recently, studies in the Sporn laboratory (23) have shownthat a fluorinated analogue of 1,250,, RO24-5531, is an effective

chemopreventive in rat mammary gland carcinogenesis. The term"deltanoid" has been suggested for active derivatives of 1,25D3 (23).

Immunomodulating Effects of 1,25D,. A number of studies haveshown that, like sunlight, derivatives of vit D have diverse effects onthe immune system, as reviewed by Manolagas et al. (106, 107).Although high concentrations of 1,250, are immunosuppressive

Table 2 Animal studies of the effects of delttinoids on minors

Reduction of carcinogen-induced lumor formation by I.25D-, or analogues

Table 1 Cultured human cells inproliferation

which deltanoiils have been reported to retard celland/or to induce differentiation

Cell line Representative studiesC'olon cancer cells

Breast cancer cells

Prostate cancer cell

Primary cultures of humanprostate cells

Keratinocytes

Melanoma cells

Leukemia cells

Lung carcinoma cells

Renal carcinoma cells

Osteosarcoma cells

Ovarian carcinoma cells

Endometrial carcinoma cells

Rctinohlastoma cells

Cross et al. (15, 60, 61). Halline et al. (62),Thomas et al. (63). Shabahang el al. (Ã>4),Zhao and Feldman (65). Wargovich andLointier (66). Lointier et al. (67)

Frampton ti al. (13), Colston et al. (14). Abeet al. (68), Colston et al. (69), James et al.(70). Desprez et al. (71), Hassan et al. (72),Demirpcnce et al. (73). Abe-Hashimoto et al.(74), Simboli-Campbell et al. (75). Roga et

al. (76). Escaleira et al. (77). Saunders et al.(78)

Miller et al. (17), Skowronski et al. (18)

Peehl et al. (19)

Sebag et al. (79)

Frampton el al. (13), Colston et al. (57)

Koeffler el al. (20), Munker et al. (21). Brelviand Studzinski (46). Reitsma et al. (47),Sherman et al. (48), McCarthy et al. (80),Tanaka el al. (81). Studzinski and Brelvi (82),Olsson et al. (83), Bhalla et al. (84). Kalo etal. (85)

Sato el al. (86)

Nagakura et al. (87)

Bonewald et al. (88), Tsuchiya et al. (89)

Saunders et al. (78), Saunders el al. (90)

Christopherson el ai (91)

Saulenas et al. (92)

Animai model" Representative studies

Rat + 1.2-dimethylhydrazine +/- high fatdiet -* colon cancer

Rat + cholic acid Â»colon cancer

Rat + lithocholic acid + NMU -Â»

colon cancer

Ral +/- high fat diet + DMBA -Â»

mammary carcinoma

Rat + NMU -â€¢mammary carcinoma

Mouse + DMBA + > skin tumors

Mouse + DMBA + TPA + Mezereinskin tumors

Pence and Buddingh (16), Beaty et al.(22). Llor et al. (93). Sitrin el al. (94),Bellcli et al. (95)

Baer and Wargovich (96)

Kawaura el al. (97)

Jacobson et al. (98), lino et al. (99)

Colston et al. (14). Anzano et al. (23).Colston et al. (69)

Wood el al. (100), Chida el al. (101)

Onda et al. (101)

Retardation of the growth of implanted xenografts by 1.25D, and/or its analogues

Immunosuppressed mouse + human colon Eisman el al. (58)carcinoma or melanomaimplants â€¢tumor growth

Nude mouse + human breast carcinomaimplant -Â»tumor growth

Nude mouse + human retinoblastomacells â€”Â»tumor growth

Abe et al. (68),Abe-Hashimoto el al. (74)

Albert et al. (102), Cohen el al. (103),Albert el al. (104)

"NMU, nitrosomethylurea; DMBA. 7,12-dimethylbenz (Â«)anthracene; TPA, 12-O-

tetradecanoylphorbol-13-acetate.

(108), vit D deficiency has a similar effect (109). This underscores theobservation that excessive exposure to sunlight is deleterious, andcompromised cellular immunity may be one of the mechanisms oftumor progression, due to either excessive or reduced levels of 1,25D,or another derivative of vit D.

Induction of Differentiation by 1,25D,

Neoplastic progression of several cell types can be reversed oraborted by induction of the differentiated phenotype, and 1,25D3 isone of the compounds effective in that respect (14, 95, 100). Forinstance, human promyelocytic leukemia cells exposed to 1,25Dâ€žalbeit at supraphysiological concentrations, differentiate into mono-cyte/macrophage-like cells (80-82). Growth arrest of cells derived

from carcinomas of the colon and prostate is also accompanied bychanges which suggest that differentiation is taking place (17, 18, 60,61). Since human tumors frequently contain a proportion of differentiated cells, an increase in the terminally differentiated cell fractionwithin a tumor would retard its growth.

Induction of Apoptosis

Another fraction of cells within a tumor undergoes cell death. Thiscan occur by necrosis, as for instance when the blood supply isinsufficient, or by apoptosis, when a program for self-destruction is

activated within a cell. A recent preliminary report indicates that1,250-, induces apoptosis in MCF-7 cells (75), which were derived

from human breast cancer. If, indeed, this is an example of a moregeneral phenomenon, it would provide yet another mechanism forsunlight, acting through 1,25D3, to retard tumor growth.

Effects of 1,25D, on Tumor Cell Invasion

Suggestive evidence that 1,25D3 can inhibit tumor spread is provided by a study of serum levels of 25D,, a vit D metabolite that mostclosely reflects endogenous production of vit Dâ€žin colonie neoplasia(110), and several reports that the geographical and racial differences

4018




in the incidence of invasive prostate cancer correlate inversely withavailability of sunlight (11, 12) and with plasma levels of vit Dmetabolites (111). These correlations are not apparent when in situtumors are considered (111-113). In one such study, approximately

250,000 serum samples were collected between 1964 and 1971 froma group of men in the Oakland-San Francisco area (111). The levels

of 25D3 and 1,25D, were measured in serum obtained from 90 blackand 91 white men, subsequently diagnosed with prostate cancer, andin control samples matched for race, age, and the day of serumcollection. Men older than 57 years with clinical prostate cancer hadprediagnosis serum levels of 1,25D3 lower than in matched controls,with a significance of P = 0.002. This difference was not seen when

latent prostate tumors were discovered accidentally at operation forbenign prostatic hyperplasia. Similarly, the fact that the latent formsof prostate cancer are equally common in black and in white men(111-113), while the incidence of clinical prostate cancer is higher in

black men, suggests that it is tumor progression that is influenced bythe lack of sunlight-generated vit D, in the heavily pigmented skin.

Experimental data also support the notion that tumor spread tendsto be limited by 1.25D,. For instance, 1,25D3 has been reported tostimulate fibronectin synthesis in several human cell lines (114) and toinhibit angiogenesis in chick embryo chorioallantoic membranes(115). Since growth of tumors and formation of metastatic nodulesrequires penetration of the extracellular matrix, followed by formationof new blood vessels, these processes present other potential mechanisms for the retardation of tumor growth by 1,25DV

Association between Sunlight and Reduced Incidence ofHuman Cancer

Several groups, principally the team led by the Garlands, haveprovided epidemiological evidence that reduced availability of sunlight correlates with an increased incidence of the carcinomas of thebreast, colon and prostate (Table 3). For instance, it was pointed outthat the incidence of these diseases is higher in the northern industrialcities in the United States compared to rural areas and Southern parts

Table 3 EpidcmioloÃ§ical Ã©videncecorrelating decreased sunlight levels anil/or dietaryintake of vitamin D with increased incidence of carcinomas of colon, breast, and

[Â¡rÃ³statein humans

OrganRepresentative

studies

ColonIncreased colon cancer rales associatedwith least natural light, e.g., geographicallocation at high latitudeIncreased risk associated with lower levelsof dietary vit D and calciumDecreased risk associated with increasedserum levels of 25D^Intake tit vit D was significantly inverselyassociated with the risk of colon cancer

BreastIncreased mortality rales associated withacid ha/e air pollutionHighest incidence in countries located athigh latitudesIncreased incidence associated withdecreased total sunlight levelsDecreased aneuploidy associated withhigh dietary intake of vit D

ProstateIncreased mortality rates associated withdecreased UV lightIncreased risk associated with higherserum levels of vit D-hinding proteinDecreased risk associated with higherlevels of serum I,25D<

CÃ¬orhamet al. (7). Garland andGarland (116)

Garland et al. (9)

Garland et al. (10)

Bostick et ni. ( 117|

CÃ¬orhamet al. (7)

CÃ¬orhamet al. (7), Garland et al. (8)

CÃ¬orhamet al. (7, 118), Garlandet al. (8)FÃ¼rstet al. (119)

Schwanz and llulka (11). Manchetteand Schwartz (12)Schwartz et al. ( 12(1)

Corder et al. ( 111)

of thÃc̈ountry (8, 12, 116). The relationship of sunlight intensity to thereduced incidence of colon cancer is complicated by its effects fromintestinal calcium; however, in Hawaii, which has abundant sunshine,calcium intake was found not to be a factor in the incidence of coloncancer, suggesting that the lack of calcium effect was due to sufficientvit D production by sunlight (121). The prospective design of thisstudy makes it particularly significant. Thus, the bulk of epidemiological evidence is inconclusive, and there is now a wealth of experimental data that makes the proposition that sunlight contributes to theretardation of cancer progression a viable one.

Racial Pigmentation and Cancer Aggressiveness

Black American men have a higher incidence of carcinoma of theprostate gland than white men, and black American women have apoorer prognosis than white women when the diagnosis of breastcancer is made (12, 111, 122). Purely genetic differences are not likelyto explain this difference, since neither white nor black Americansrepresent a single genetic pool but are a mixture of races (123). It wasnoted above that only the aggressive, clinically apparent cases ofprostatic carcinoma have a higher incidence in black than in whitemen, the incidence of in situ carcinoma being the same (111-113). A

recent study suggests that socioeconomic factors are insufficient toexplain these differences. Hispanic women, who as a group have asimilar socioeconomic background to black women, had less aggressive carcinoma of the breast than black women but more aggressivethan white women (122). In this study, the aggressiveness of tumorcells correlated with the degree of skin pigmentation, consistent withour hypothesis that sunlight-generated vit D metabolites retard tumor

progression. It was also reported that racial pigmentation determinesthe magnitude of the increase in serum vit D, levels followingwhole-body exposure to UVB irradiation, being highest in whites and

lowest in blacks (124). Serum levels of 25D, increased in the irradiated individuals in an inverse proportion to skin pigmentation (lowestin blacks, then Indians, Orientals, and highest in whites). Increasedlevels of 1,25D, were not detected, but the basal serum levels were inthe mid-normal range in all groups, consistent with the regulation of

serum levels of 1,25D, by its hydroxylation at the la position in thekidney and with the observation that UV irradiation increases circulating levels of 1,25D, only in people who are vit D deficient (125).A similar study on individuals with low circulating levels of 1,25D,would provide a better test of our hypothesis. It would also beinteresting to determine, under laboratory conditions, if 25D, also hasa direct retarding effect on tumor progression or if it only provides areservoir for conversion to 1,25D,. A recent report by Bell el al. (126)suggests that 25D may be bioactive, since it appears to regulatecalcium metabolism independently of 1.25D. Since in blacks serum25D levels were found to be reduced but 1,25D (the sum of 1,250,and 1,25D3) were not, circulating 25D3 may be the form of vit Dimportant for the antitumor progression activity. A possible mechanism is provided by the finding that a number of cells, includingmacrophages, can convert 25D, to 1,25D3 (127), and many tumors areinfiltrated by macrophages. Thus, tumor macrophages may play sucha role and aid in retardation of tumor progression. Further studies oftumor cell biology in relation to racial origin seem clearly desirable.

Summary and Implications

Evidence is summarized that sunlight-generated derivatives of vit

D, most likely 1,25D,, may alter the progression of several types ofhuman neoplastic disease. The proposed mechanisms include immu-

nosuppression, which may raise the incidence of skin cancer when sunexposure is excessive, or cause accelerated tumor progression in vit D

4019



.SUNLIGHT: PRKVKNTION OF CANCKR

deficiency. Sunlight exposure optimal for health depends on the skinpigmentation of the individual and the individual's race.

One consequence of these considerations is that advice regardingthe use of sunscreen should be given with caution. A recent reportdocuments that sunscreens did not reduce the incidence of skin cancerin UV-irradiated mice, and the authors warn that the use of sunscreens

can result in a sense of false security (128, 129). Apart from thepotential presence of irritants in sunscreen, particularly harmful whenin contact with the mucosal surfaces or with skin allergic to chemicals,the desirability of sunscreen use will depend on individual circumstances. Relevant factors include the intensity of the anticipated sunlight exposure, the skin pigmentation of the individual, and the individual's race. The amount of sunlight exposure that is appropriate for

a lightly pigmented person may be insufficient for a darkly pigmcntedindividual. Thus, warning about the dangers of sunlight should betempered by these considerations.

Another unresolved issue is to what extent vit D should be includedas a dietary supplement in frequently consumed foods. Certainly, thecurrent recommendations that the recommended daily allowance of 10fxg vit D (400 lU) for children older than 6 months and young adultsbe reduced to 5 /ig (200 1U) for people over the age of 24 may bereasonable if prevention of rickets is the only objective (130). However, this recommended daily allowance for older people may need tobe increased if the cancer chemopreventive role of vit D is accepted,since the risk of developing cancer is much greater in older adults thanin children and young adults, and the skin's ability to convert 7-DHC

to 1.25D., declines with age (30).Although there is as yet no definitive proof for the belief that

sunlight and vit D protect humans from the development and progression of carcinomas of the breast, prostate, and/or colon, experimentaldata support the limited number of epidemiological studies that areconsistent with the hypothesis that sunlight-generated vit D deriva

tives contribute to a lower incidence of the clinically apparent formsof these malignancies. Importantly, there are plausible mechanismsthat can explain the retardation of cancer progression by vit D metabolites. Thus, study of the beneficial effects of sunlight on cancerprogression should be removed from the realm of mysticism andthrust in to the scientific arena of experimental studies.

Acknowledgments

We thank our colleagues Drs. John Bogden, John Bullock, W. ClarkLambert, Donald Louria, Gabriel Mulcahy. Robert Schwartz, and Dr. MilanUskokovic (Hoffmann-LaRoche, Nutley, NJ) for the critical reading of this 29

manuscript.

References

1. Koh. H. K-, Kliglcr, B. E.. and Lew. R. A. Sunlight and cutaneous malignant melanoma:evidence for and against causation. Photochem. Photohiol., SI: 765-779. 199(1.

2. Hnlman, C. D.. and Armstrong. B. K. Cutaneous malignant melanoma and indicatorsof total accumulated exposure to the sun: an analysis separating histogenetic types.J. Nati. Cancer Inst., 7.ÃŒ:75-82, 1986.

3. Movshovitz, M., and Modan, B. Role of sun exposure in the etiology of malignantmelanoma: epidemiologie inference. J. Nati. Cancer Inst.. 51: 777-779, 1973.

4. Ainsleigh, G. H. Beneficial effects of sun exposure on cancer mortality. Prev. Med.,22: 132-140, 1993.

5. Mozolowski. W. Jedrzej Sniadecki (1768-1883) on the cure of rickets. Nature(Lond.), 143: 121, 1939.

6. McCollum, E., Simmnnds, N., Becker, J. E.. and Shipley, P. G. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitaminwhich promotes calcium deposition. J. Biol. Chem., 53: 293-312, 1922.

7. Ciorham. E. D., Garland. C. F., and Garland, F. C. Acid haze air pollution and breastand colon cancer mortality in 20 Canadian cities. Can. J. Public Health, HO:96-HX),

19X9.H. Garland, F. C., Garland, C. F., Gorham, E. D., and Young. J. F. Geographic variation

in breast eaneer mortality in the United States: a hypothesis involving exposure tosolar radiation. Prev. Med., IV: 614-622, 1990.

9. Garland, C., Shckclle, R. B., Barret-Connor, E., Criqui, M. H., Rossof, A. H., andOglesby, P. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-yearprospective study in men. Lancet. /: 307-309. 1985.

4020

10. Garland, C. F.. Comstock, G. W., Garland. F. C, Helsing. K. J.. Shaw, E. K., andGorham. E. D. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet, 2: 1176-1178, 1989.

11. Schwartz, G. G.. and Hulka, B. S. Is vitamin D deficiency a risk factor for prostatecancer (Hypothesis)? Anticancer Res., 10: 1307-1312, 1990.

12. Hanchette, C. L., and Schwartz. G. G. Geographic patterns of prostate cancermortality. Cancer (Phila.), 70: 2861-2869. 1992.

13. Frampton. R. J.. Omond. S. A., and Eisman. J. A. Inhibition of human cancer cellgrowth by 1.25-dihydroxyvitamin D, metabolites. Cancer Res., 43: 4443-4447,1983.

14. Colston. K. W.. Mackay, A. G., James, S. Y., Binderup, 1... Chander. S., andCoombes, R. C. EB1089: a new vitamin D analogue that inhibits the growth ofbreast cancer cells in vivo and in vitro. Biochem. Pharmacol.. 44: 2273-2280. 1992.

15. Cross, H. S., Huber. C., and Peterlik. M. Antiproliferative effect of 1,25-dihy-droxyvitamin D, and its analogs on human colon adenoearcinoma cells (CACO- 2):influence of extracellular calcium. Biochem. Biophys. Res. Commun.. 779: 57-62,

1991.16. Pence, B. C., and Buddingh, F. Inhibition of dietary fat-promoted colon earcino-

gcnesis in rats by supplemental calcium or vitamin D,. Carcinogencsis (Lond.). u:187-190, 1988.

17. Miller. G. J., Stapelton, G. E., Ferrara, J. A.. Lucia, M. S., Pfister, S., Hedlund, T.E., and Upadhyaya, P. The human prostatic carcinoma cell line LNCaP expressesbiologically active, specific receptors for ltt.25-dihydroxyvitamin Dv Cancer Res..52: 515-520, 1992.

18. Skowronski. R. J., Peehl, D. M., and Feldman, D. Vitamin D and prostate cancer:1.25 dihydroxyvitamin D, receptors and actions in human prostate cancer cell lines.Endocrinology, 132: 1952-1960. 1993.

19. Peehl. D. M., Skowronski, R. J.. Leung, G. K., Wong, S. T., Stamey, T. A., andFeldman. D. Antiproliferative effects of 1,25-dihydroxyvitamin D^ on primarycultures of human prostatic cells. Cancer Res., 54: 805-810, 1994.

20. Kocffler, H. P.. Hirji. K.. and Itri, L. Southern California Leukemia Group. 1,25-dihydroxyvitamin D,: in vivo and in vitro effects on human preleukemie andIcukemic cells. Cancer Treat. Rep., 69: 1399-1407, 1985.

21. Munker. R.. Norman. A., and Koeffler. H. P. Vitamin D compounds. Effect onclonal proliferation and differentiation of human myeloid cells. J. Clin. Invest., 78:424-430, 1986.

22. Beaty. M. M., Lee. E. Y.. and Glauert. H. P. Influence of dietary calcium andvitamin D on colon epithelial cell proliferation and 1,2-dimethylhydrazine-inducedcolon carcinogcnesis in rats fed high fat diets. J. Nutr., 123: 144-152, 1993.

23. Anzano, M. A.. Smith. J. M.. Uskokovic. M. R., Peer, C. W.. Mullen. L. T.. Lctterio,J. J.. Welsh, M. C.. Shrader, M. W.. Logsdon. D. L.. Driver. C. L.. Brown, C. C.,Roberts. A. B., and Sporn. M. B. lÂ«,25-dihydroxy-16-ene-23-yne-26,27-hcxafluo-rocholecalciferol (Ro24-5531), a new deltanoid (vitamin D analogue) for prevention of breast cancer in the rat. Cancer Res., 54: 1653-1656, 1994.

24. Moskowitz. M. A., and Wurlman, R. J. New approaches to the study of the humanpineal organ. In: J. M. B. Bloodworth (ed.). Endocrine Pathology, Ed. 2, pp.133-154, 1982.

25. Donawho, C. K., and Kripke. M. L. Evidence that the local effect of ultravioletradiation on the growth of murine melanomas is immunologically mediated. CancerRes.. 51: 4176-4181, 1991.

26. Herscy, P., Hasic, E.. Edwards, A., Bradley, M.. liaran. G., and McCarthy, W. H.Immunological effects of solarium exposure. Lancet. /: 545-548. 1983.

27. Rivers, J. K., Norris, P. G., Murphy. G. M., Chu, A. C. Midgley. G., Morris, J.,Morris, R. W.. Young, A. R., and Hank. J. L. M. UVA sunbcds: tanning, photo-protection, acute adverse effects and immunological changes. Br. J. Dermatol., 720:767-777, 1989.Kripke, M. L. Ultraviolet radiation and immunology: something new under the sun.Cancer Res., 54: 6102-6105. 1994.

Lcrner, A. B., Case, J. D.. Takahashi, Y.. Lee, T. H., and Mori, W. Isolation ofmelatonin, the pineal gland factor that lightens melanocytes. J. Am. Chem. Sac.. XO:2587. 1958.

30. Webb, A. R., and Holick, M. F. The role of sunlight in the cutaneous production ofvitamin D,. Annu. Rev. Nutr., 8: 375-399, 1988.

31. Walters, M. R. Newly identified actions of the vitamin D endocrine system. Endocr.Rev., 13: 719-764. 1992.

32. Stumpf, W. E. Vitamin D-Soltriol. The heliogenic steroid hormone: somatotrophieactivator and modulator. Histochemistry. W: 209-219, 1988.

33. Tanaka. Y.. Castillo, L.. and DeLuca, H. F. Control of renal vitamin D hydroxylasein birds by sex hormones. Proc. Nati. Acad. Sci. USA, 73: 2701-2705, 1976.

34. Spanos, E., Colston, K. W., Evans, I. M. S., Galante, L. S., MacAuley. S. J.. andMaclntyre, I. Effects of prolactin on vitamin D metabolism. Mol. Cell. Endocrinol.,5: 163-167, 1976.

35. Salamone. L. M., Dallai, G. E., Zantos. D., Makraucr F.. and Dawson-I lughes. B.Contributions of vitamin D intake and seasonal sunlight exposure to plasma 25-hydroxyvitamin D concentration in elderly women. Am. J. Clin. Nutr., 5<S:80-86, 1993.

36. Webb, A. R., Pilbeam C., Hanafin, N., and Holick, M. F. An evaluation of therelative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston.Am. J. Clin. Nutr., 51: 1075-1081, 1990.

37. Norman, A. W., Roth, J.. and Orci. L. The role of the vitamin D endocrine systemsteroid metabolism, hormone receptors, and biological response (calcium-bindingprotein). Endocr. Rev., 3: 331-366, 1982.

38. Henry, H. L., and Norman, A. W. Vitamin D metabolism and biological actions.Annu. Rev. Nutr., 6: 527-562, 1986.

39. Holick, M. F., Shao, 0., Liu, W. W.. and Chen, T. C. The vitamin D content offortified milk and infant formula. N. Engl. J. Med.. 32f>: 1178-1181, 1992.

28.




4(1. Reichel. H.. Koefflcr. H. P., and Norman. A. W. The role of the vitamin D endocrine 70.system in health and disease. N. Engl. J. Med., 320: 980-991, 1989.

41. Studzinski. G. P.. McLane. J. A., and Uskokovic. M. R. Signaling pathways forvitamin D-induced differentiation: implications for therapy of proliferalivc and 71.neoplastic diseases. Crit. Rev. Eukaryotic Gene Expression, 3: 279-312, 1993.

42. Umesono, K., Murakami, K. K.. Thompson. C. C.. and Evans, R. M. Direct repeatsas selective response elements for the thyroid hormone, retinoic acid, and vitamin D,receptors. Cell, 65: 1255-1266, 1991. 72.

43. Manolagas, S. C. Vitamin D and its relevance to cancer. Anticancer Res., 7:625-638, 1987.

44. Calverley, M. J., and Jones, G. Vitamin D. In: R. T. Blickenstaff (Ã©d.).Antilumor 73.Steroids, pp. 193-220, Orlando, FL: Academic Press. 1992.

45. Price, P. A., and Raukol. S. A. 1,25-Dihydroxyvitamin D, stimulates the alkalinephosphatasc activity of osteohlast-like bone tumor cells. J. Biol. Chem., 256:7115-7117. 1981. 74.

46. Brelvi, Z. S.. and Studzinski. G. P. Changes in the expression of oncogenes encodingnuclear phosphoproteins hut not c-Ha-ru.s have a relationship to monocytic differentiation of HL 6(1 cells. J. Cell. Biol.. 102: 2234-2243, 1986.

47. Reitsma. P. H., Rothnerg, P. G., Aslrin. S. M., Triol, J., Bar-shavit. Z., Hall. A.. 75.Teitelhaum. S. L.. and Kahn. A. J. Regulation of c-mvr gene expression in HL-60leukemia cells by a vitamin D metabolite. Nature (Lond.). 306: 492-494, 1983.

48. Sherman. M. L., Stone. R. M.. Datta. R., Bernstein, S. H.. and Kufe. D. W. 76.Transcriptional and posttranscriptional regulation of c-jun expression during monocytic differentiation of human mveloid leukemic cells, j. Biol. Chem., 265:3320-3323, 199(1. 77.

49. Studzinski, G. P., Brelvi, Z. S., Feldman, S. C., and Watt, R. A. Participation ofc-mvr protein in DNA synthesis of human cells. Science (Washington DC), 234:467-470, 1986. 78.

50. Callahan. R., and Campbell. G. Mutations in human breast cancer: an overview. J.Nati. Cancer. Inst., 81: 1780-1786, 1989.

51. Minghetti, P. P.. and Norman. A. W. 1,25(OH)2-Vitamin D, receptors: generegulation and genetic circuitry. FASEB J., 2: 3043-3053, 1988. 79.

52. Foulds. L. Neoplastic development. New York: Academic Press, 1969.53. Nowcll. P. C. The clonal evolution of tumor cell populations: acquired genetic

lability permits stepwisc selection of variant sublines and underlies tumor progres- 80.sion. Science (Washington DC), Â¡94:23-28, 1976.

54. Studzinski. Ci. P. Oncogenes, growth, and the cell cycle: an overview. Cell TissueKinet., 22: 405-424, 1989.

55. Studzinski. G. P.. Moore. D. C., and Carter, D. L. Suppressor genes; restraint of 81.growth or of tumor progression? Lab. Invest., 63: 279-282, 1990.

56. Cornwell, M. L., Comstock, G. W.. Holick. M. F.. and Bush, T. L. Prediagnosticserum levels of 1,25-dihydroxyvitamin D and malignant melanoma. Photodermatol.Photoimmunol. Photomed.. 9: 109-112, 1992. 82.

57. Colston. K., Colston. M. J., and Feldman, D. 1,25-Dihydroxyvitamin D, andmalignant melanoma: the presence of receptors and inhibition of cell growth inculture. Endocrinology, KM: 1083-1086, 1981. 83.

58. Eisman. J. A.. Barkla. D. H., and Tutton. P. J. M. Suppression of in vivo growth ofhuman cancer solid tumor xenografts by 1,25-dihydroxyvitamin D, Cancer Res..47: 21-25, 1987. 84.

59. Koh. H. K.. Michalik, E., Sober. A. J., Lew, R. A., Day, C. L.. Clark, W., Mihm. M.C.. Kopf, A. W., Blois, M. S., and Fitzpatrick, T. B. Lentigo maligna melanoma hasno better prognosis than other types of melanoma. J. Clin. Oncol., 2: 994-1000, 85.

1984.60. Cross, H. S., Pavelka. M., Slavik, J., and Peterlik, M. Growth control of human colon

cancer cells by vitamin D and calcium in vitro. J. Nati. Cancer Inst., 84: 1355-1357,1992. 86.

61. Cross, H. S., Farsoudi. K. H.. and Peterlik. M. Growth inhibition of human colonadenocarcinoma-derived Caco-2 cells by 1,25-dihydroxyvitamin D, and two syn- 87.

thetic analogs: relation to in vitro hypercalcÃ©miepotential. Arch. Pharmacol.. 437:105-110, 1993.

62. Halline, A. G., Davidson. N. O., Skarosi, S. F., Sitrin, M. D., Tietze. C.. Alpers, 88.D. H., and Brasitus, T. A. Effects of 1,25-dihydroxyvitamin D3 on proliferation anddifferentiation of CACO-2 cells. Endocrinology, 134: 1710-ÃŒ717. 1994.

63. Thomas. M. G., Tebbutt, S., and Williamson. R. C. N. Vitamin D and its metabolitesinhibit cell proliferation in human rectal mucosa and a colon cancer cell line. Gut, 89.33: 1660-1663. 1992.

64. Shabahang. M., Buras, R. R., Davoodi, F., Schumaker, L. M., Nauta. R. J., andEvans, S. R. T. 1.25-dihydroxyvitamin D, receptor as a marker of human colon 90.carcinoma cell line differentiation and growth inhibition. Cancer Res.. 53: 3712-3718, 1993.

65. Zhao, X., and Feldman, D. Regulation of vitamin D receptor abundance and 91.responsiveness during differentiation of HT-20 human colon cancer cells. Endocrinology, 132: 1808-1814. 1993.

66. Wargovich. M. J., and Lointier, P. H. Calcium and vitamin D modulate mouse colon 92.epithelial proliferation and growth characteristics of a human colon tumor cell line.Can. J. Physiol. Pharmacol., 65: 472-477, 1987.

67. Lointier, P.. Wargovich, M. J., Saez, S.. Levin, B., Wildrick, M.. and Boman, B. M. 93.The role of vitamin D, in the proliferation of a human colon cancer cell line in vi/rn.Anticancer Res., 7: 817-822, 1987.

68. Abe, J., Nakano, T.. Nishii, Y., Matsumolo, T.. Ogata, E., and Ikeda. K. A novelvitamin D, analog, 22-oxa-l,25-dihydroxyvitamin D,, inhibits the growth of human 94.breast cancer in vitro and in vivo without causing hypercalcemia. Endocrinology.129: 832-837, 1991.

69. Colston, K. W., Chander, S. K., Mackay. A. G., and Coombes, R. C. Effects of 95.synthetic vitamin D analogues on breast cancer cell proliferation m vÃ¬voand in vitro.Biochem. Pharmacol., 44: 693-702, 1992.

4021

James, S. Y.. Mackay. A. G.. Ofori-Kuragu, E. A.. Binderup, L.. and Colston. K. W.Effects of F,B1089. a new synthetic vitamin D analogue, on the estrogen-responsivegrowth of human breast cancer cells. J. Endocrino!., 135: 21. 1992.Desprez, P. Y., Poujol, D., and Saez, S. Glyccraldehyde-3-phosphate dehydrogenasc

(GAPDH, E.G. 1.2.1.12.) gene expression in two malignant human mammaryepithelial cells lines: BT-20 and MCF-7. Regulation of gene expression by 1,25-dihydroxyvitamin Dv Cancer Lett., 64: 219-224, 1992.

Hassan. H. T.. Eliopoulos. A.. Maurer, H. R.. and Spandidos. D. A. Recombinanthuman GM-CSF enhances the anti-proliferative activity of vitamin D in MCF-7human breast cancer clonogenic cells. Eur. J. Cancer. 28: 1588-1589, 1992.

Dcmirpence, E.. Balaguer, P.. Trousse, F.. Nicolas, J. C.. Pons, M., and Gagne, D.Antiestrogenic effects of all-/rÂ«Â«.v-retinoicacid and 1,25-dihydroxyvitamin D, in

breast cancer cells occur at the estrogen response element level but through differentmolecular mechanisms. Cancer Res., 54: 1458-1464. 1994.Abe-Hashimoto, J., Kikuchi, T., Matsumoto, T., Nishii. Y., Ogata, E.. and Ikcda, K.Antitumor effect of 22-oxa-calcitriol, a noncalcemic analogue of calcitriol. in thymic

mice implanted with human breast carcinoma and its synergism with tamoxifcn.Cancer Res., 53: 2534-2537, 1993.Simboli-Campbell, M., Welsh, J., and Tenniswood. M. P. R. Effect of 1.25-dihydroxyvitamin D, on proliferation and apoptosis in MCF-7 breast cancer cells. J.Cell. Biochem. Abs. Suppl., 18D: 245, 1994.Koga, M.. Eisman, J. A., and Sutherland, R. L. Regulation of epidermal growthfactor receptor levels by 1.25-dihydroxyvitamin D, in human breast cancer cells.Cancer Res., 48: 2734-2739, 1988.Escalcira, M. T. F., Sonohara, S., and Brentani, M. M. Sex steroids inducedup-regulation of 1.25-(OH), vitamin D, receptors in T 47D breast cancer cells. J.Steroid Biochem. Mol. BioL, 45: 257-263, 1993.Saunders, D. E., Christensen. C., Wappler, N. L., Schultz, J. F., Lawrence. W. D..Malviva. V. K., Malone. J. M., and Deppe, G. Inhibition of c-mvc in breast andovarian carcinoma cells by 1.25-dihydroxyvitamin D, retinoic acid and dexametha-sone. Anti-Cancer Drugs, 4: 201-208. 1993.Scbag. M., Henderson, J., Rhim. J., and Kremer. R. Relative resistance to 1,25-

dihydroxyvitamin D} in a keratinocyte model of tumor progression. J. Biol. Chem..267: 12162-12167, 1992.

McCarthy, D. M., San Miguel, J. F., Freake. H. C.. Green, P. M.. Zola, H., Catonsky, D.,and Goldman, J. M. 1,25-Dihydroxyvitamin D, inhibits proliferation of human promy-elocytic leukemia (HL60) cells and induces monocyte-macrophage differentiation inHL60 and normal human bone marrow cells. Leuk. Res., 7: 51-55. 1983.Tanaka, H., Abe. E.. Miyaura, C.. Shiina. Y., and Suda, T. lor.25-DihydroxyvitaminD, induces differentiation of human promyelocytic leukemia cells (HL-60) intomonocytc-macrophages, but not into granulocytes. Biochem. Biophys. Res.Commun.. 117: 86-92. 1973.Studzinski. G. P., and Brelvi, Z. S. Changes in proto-oncogene expression associatedwith reversal of macrophage-like differentiation of HL60 cells. J. Nati. Cancer. Inst..79: 67-76, 1987.

Olsson. I.. Gullberg, U., Ivhed, !.. and Nilsson, K. Induction of differentiation of thehuman histiocytic lymphoma cell line U-937 by la,25-dihydroxycholecalciferol.Cancer Res., 43: 5862-5867. 1983.Bhalla. A. K.. Williams. M. M.. Lai. S.. and Lydyard. P. M. 1.25-Dihydroxyvitamin

D,, but not retinoic acid, induces the differentiation of U937 cells. Clin. Exp.Immunol.. 76: 274-277, 1989.Kato, H.. Adachi, K., Suzuki. M.. Tanimoto, M., and Saito, H. Macrophage colon-stimulating factor stimulates growth progession of the G,-phase fraction and inducesmonocytic differentiation of the G^/M-phase fraction in human myeloid leukemiacells. Exp. Hematol., 21: 1597-1604, 1993.

Sato, T.. Takusagawa. K., Asoo, N., and Konno. K. Antitumor effect of lo>hydroxyvitamin D,. Tohoku J. Exp. Med., 138: 445-446, 1982.

Nagakura. K., Abe. E., Suda, T., Hayakawa, M.. Nakamura. H.. and Tazaki. H.Inhibitory effect of Ia25-dihydroxyvitamin D^ on the growth of the renal carcinomacell line. Kidney Int., 29: 834-840, 1986.Bonewald, L. F., Kester, M. B.. Schwartz. Z., Swain, L. D., Khare. A.. Johnson, T.L.. Leach, R. J., and Boyan, B. D. Effects of combining transforming growth factorÃŸand 1.25-dihydroxyvitamin D, on differentiation of a human osteosarcoma (MG-63). J. Biol. Chem.. 267: 8943-8949, 1992.

Tsuchiya. H., Morishita. H., Tornita. K.. Ueda, Y., and Tanaka. M. Differentiatingand antitumor activities of la,25-dihydroxyvitamin D^ in vitro and la-hydroxyvi-tamin D, in vivtt on human osteosarcoma. J. Orthop. Res., //: 122-130. 1993.Saunders, D. E., Christensen, C., Lawrence, W. D., Malviva, V. K.. Malone, J. M..Williams, J. R., and Deppe, G. Receptors for 1.25-dihydroxyvitamin D, in gynecologic neoplasms. Gynecol. Oncol.. 44: 131-136, 1992.Christopherson. W. A., Porter. J. C.. MacDonald. P. C., and Casey, M. L. Responsiveness of human carcinoma cells of gynecologic origin to 1.25- dihydroxychole-calciferol. Am. J. Obstet. Gynecol., 155: 1293-1296, 1986.Saulenas, A. M., Cohen, S. M., Key, L. L., Winter, C., and Albert, D. M. VitaminD and retinohlastoma: the presence of receptors and inhibition of growth in vilrn.Arch. Ophthalmol., 106: 533-535. 1988.Llor. X., Jacoby, R. F., Teng, B. B., Davidson, N. O., Sitrin. M. D., and Brasitus,T. A. K-ra.v mutations in 1,2-dimethylhydrazine-induced colonie tumors: effects ofsupplemental dietary calcium and vitamin D deficiency. C'ancer Res., 51: 4305-

4309. 1991.Sitrin. M. D., Halline. A. G.. Abrahams, C., and Brasitus, T. A. Dietary calcium andvitamin D modulate 1,2-dimcthylhydrazine-induced colonie carcinogcnesis in therat. Cancer Res., 51: 5608-5613, 1991.

Bellcli. A., Shany, S., Levy, J., Guberman, R., and Lamprccht, S. A. A protectiverole of 1,25-dihydroxyvitamin D, in chemically induced rat coltin carcinogenesis.Carcinogcnesis (Lond.). 13: 2293-2298, 1992.




96. Bacr. A. R.. and Wargovich, M. J. Dietary calcium and vitamin I), inhibit colonieornilhinc decarhoxylase activity induced hy bile acids. FASEB J., A469, 1989. 114.

97. Kawaura. A., TaÃ±ida.N., Sawada. K., Oda. M., and Shimoyama. T. Supplementaladministration of hr-hydroxyvitamin D, inhibits promotion by intrarcclal instillation of lithocholic acid in A^-methyl-W-nitrosourea-induced colonie tumorigcnesis in 115.rals. Carcinogencsis (Lond.), 10: 647-649, 1989.

98. Jacobson. E. A.. James, K. A., Newmark, H. L. and Carroll. K. K. Effects of dietaryfat, calcium, and vitamin D on growth and mammary tumorigenesis induced by 116.7,12-dimethylbenz(<i)anlhracene in female Spraguc-Dawlcy rats. Cancer Res., 49:6300-6303, 1989. 117.

99. lino. Y., Yoshida. M.. Sugamata. N., Maemura. M., Ohwada, S.. Yokoe. T., Ishikita.T., Horiuchi. R.. and Morishita. Y. la-hydroxyvitamin D,, hypercalcemia, andgrowth suppression of 7.l2-dimcthylbenz[ii]anthracene-induced rat mammary tu- l IS.mors. Breast Cancer Res. Treat.. 22: 133-140, 1992.

100. Wcxid, A. W.. Chang, R. L.. Huang, M. T., Uskokovic, M.. and Conncy, A. H. 119.Itt25-Dihydroxyvitamin D, inhibits phorbol ester-dependent chemical carcinogcn-esis in mouse skin. Biochem. Biophys. Res. Commun., 116: 605-611, 1983. 120.

101. Chida, K.. Hashiha. H., Fukushima, M.. Suda, T.. and Kuroki. T. Inhibition of tumorpromotion in mouse skin by l<r,25-dihydroxyvitamin D,. Cancer Res., 45: 5426- 121.5430. 1985.

102. Albert. D. M.. Saulenas, A. M., and Cohen, S. M. Vcrhoeff's query: is vitamin D

effective against retinohlasloma? Arch. Ophthalmol., 106: 536-540. 1988. 122.103. Cohen. S. M., Saulenas, A. M., Sullivan, C. R., and Albert, D. M. Further studies of

the effect of vitamin D on retinohlasloma: inhibition with 1.25-dihydroxycholecal-ciferol. Arch. Ophlhalmol.. 106: 541-543. 1988. 123.

104. Albert, D. M., Marcus, D. M., Gallo, J. P., and O'Brien, J. M. The antineoplastic

effect of vitamin D in Iransgenic mice with retinoblastoma. Invest. Ophthalmol. Vis.Sci., 33: 2354-2364, 1992. 124.

105. Newmark, H. L., and Lipkin, M. Calcium, vitamin D, and colon cancer. Cancer Res.,52: 2067-2070, 1992.

106. Manolagas, S. C, Provvedini, D. M., and Tsoukas, C. D. 1,25-Dihydroxyvitamin D, 125.and immune system. Mol. Cell. Endocrinol., 43: 113-122. 1985.

107. Manolagas, S. C, Yu, X-P.. Girasole, G., and Bellido, T. Vitamin D and thehematolymphopoictic tissue: a 1994 update. Semin. Ncphrol.. 14: 129-143, 1994. 126.

108. Yang. S.. Smith. C., and DeLuca. H. F. 1 a,25-Dihydroxyvitamin D, and 19-nor-la,25 dihydroxyvitamin D, suppress immunoglobulin production and Ihymic lymphocyte proliferation in viva. Biochem. Biophys. Acta. II5X: 279-286, 1993. 127.

109. Yang S.. Smith. C.. Prahl, J. M., Luo. X., and DeLuca. H. F. Vit D deficiency suppressescell-mediated immunity in rm>. Arch. Biochem. Biophys., 303: 98-106, 1993.

110. Glass, A. R., Kikendall, J. W., Sobin, L. H., and Bowen, P. E. Serum 25-hydroxyvi-tamin D concentrations in colonie neoplasia. Horm. Metab. Res.. 25: 397-398. 1993.

111. Corder, E. H., Guess, H. A., and Hulka, B. S. Vitamin D and prostate cancer: a 128.prediagnostic study with stored sera. Cancer Epidemiol., Biomarkers & Prev., 2:467-472, 1993.

112. Chiarodo, A. National Cancer Institute roundtahle on prostate cancer: future research 129.directions. Cancer Res., SI: 2498-2505, 1991.

113. Breslow, N., Chan, C. W., Dhom, G., Drury, R. A. B.. Franks, L. M.. Gellei. B., Lee, 130.Y. S., Lundberg, S., Sparke, B.. Slernby, N. H., and Tulinius. H. Latent carcinoma

of prostate at autopsy in seven areas. Int. J. Cancer, 2(1: 680-688. 1977.Franceschi. R. T.. Linson, C. J., Peter, C'. J., and Romano. P. R. Regulation of

cellular adhesion and tihronectin synthesis hy l-Â«.25-dihydroxyvitamin D,. J. Biol.Chem., 262: 4165-4171. 1987.Oikawa. T.. Hirotani. K.. Ogasawara. H.. Katayama. T., Nakamura. O., Iwaguchi, T.,and Hiragun, A. Inhibition of angiogenesis by vitamin D, analogues. Eur. J.Pharmacol., Â¡7X:247-250, 1990.

Garland. C. F.. and Garland. F. C. Do sunlight and vitamin D reduce the likelihoodof colon cancer? Int. J. Epidemiol., 9: 227-231. 1980.Boslick. R. M.. Potter. J. D., Sellers, T. A., McKenzie. D. R.. Kushi L. H.. andFolsom A. R. Relation of calcium, vitamin I), and dairy food intake to incidence ofcolon cancer among older women. Am. J. Epidemiol., 137: 1302-1317. 1993.Gorham, E. D.. Garland. F. C.. and Garland, C. F. Sunlight and breast cancerincidence in the USSR. Int. J. Epidemiol., /9: 820-924, 1990.

FÃ¼rst,C. J.. Auer. G.. Nordevang. E., Nilsson, B.. and Holm, L. Ã•Ã•.DNA pattern anddietary habits in patients with breast cancer. Eur. J. Cancer. 29: 1285-1288. 1993.

Schwartz, G. G.. Hulka, B. S., Morris. D., and Mohler, J. L. Prostate cancer andvitamin (hormone) D: a case control study. J. Urol.. (Suppl.)/^7: 294A. 1992.Heilbrun. L. K., llankin. J. J., Nomura, A. M. Y., and Stemmermann. G. N. Coloncancer and dietary fat. phosphorus, and calcium in Hawaiian-Japanese men. Am. J.Clin. Nutr., 43: 3(16-309. 1986.

Ellcdge, R. M., Clark, G. M., Chamness, G. C.. and Osborne, C. K. Tumor biologicfactors and breast cancer prognosis among white, Hispanic, and black women in theUnited States. J. Nati. Cancer Inst., X6: 705-712, 1994.

Nagel. R. L.. Fabry. M. E.. Pagnier. J.. Zohoun. !.. Wajcman, H., Baudin V., andLabie, D. Hcmatologically and genetically distinct forms of sickle cell anemia inAfrica. N. Engl. J. Med.. 312: 880-884, ÃŒ985.

Matusoka, L. Y.. Wortsman, J.. Haddad, J. G., Kolm. P.. and Mollis, B. W. Racialpigmentation and the cutaneous synthesis of vitamin D. Arch. Dermatol.. 127:536-538, 1991.Adams, J. S., Clemens. T. L., Parrish, J. A., and Holick, M. F. Vitamin-D synthesisand metabolism after ultraviolet irradiation of normal and vitamin D-deficientsubjects. N. Engl. J. Mcd.. 306: 722-725. 1982.

Bell. N. H., Green A., Epstein S., Oexmann. M. J.. Shaw. S.. and Shary J. Evidencefor alteration of the vitamin D-endocrine system in blacks. J. C'lin. Invest.. 76;

470-473, 1985.

Hayes, M. E.. Bayley. D., Drayson, M.. Freemont. A. J., DentÃ³n.J.. Davics, M.. andMawer. E. B. Metabolism of 25-hydroxyvitamin Dt to 24,25-dihydroxyvitamin D,

by blood derived macrophages from a patient with alveolar rhabdomyosarcomaduring short-term culture and l-a.25-dihydroxyvitamin D, after long-term culture.J. Steroid Biochem. Mol. Biol., 3H: 301-306, 1991.Wolf. P., Donawho. C'. K.. and Kripke. M. L. Effect of sunscreens on UV radiation

induced enhancement of melanoma growth in mice. J. Nail. Cancer Inst., 86:99-105, 1994.Koh. H. K., and Lew, R. A. Sunscreens and melanoma: implications for prevention.J. Nail. Cancer Inst., 86: 78-79, 1989.Recommended Dietary Allowances, pp. 93â€”99.Washington, DC: National Aca

demic Press. 1989.

4022



1995;55:4014-4022. Cancer Res George P. Studzinski and Dorothy C. Moore

Can It Prevent as well as Cause Cancer?−−Sunlight

Updated version

http://cancerres.aacrjournals.org/content/55/18/4014

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/55/18/4014To request permission to re-use all or part of this article, use this link



http://cancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]



Sunlightâ€”Can It Prevent as well as Cause Cancer?1 · SUNLIGHT: PREVENTION OF CANCER Fig. 2....

Documents

Transcript of Sunlightâ€”Can It Prevent as well as Cause Cancer?1 · SUNLIGHT: PREVENTION OF CANCER Fig. 2....